Bicyclic heteroaryl substituted compounds

ABSTRACT

Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to 3 R 3a ; and R 1 , R 2 , R 3a , R 4 , and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to priority pursuant to 35 U.S.C. § 119(e)to U.S. provisional patent application No. 62/362,113, filed Jul. 14,2016, which is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to bicyclic heteroarylsubstituted compounds useful as inhibitors of platelet aggregation.Provided herein are bicyclic heteroaryl substituted compounds,compositions comprising such compounds, and methods of their use. Theinvention further pertains to pharmaceutical compositions containing atleast one compound according to the invention that are useful inpreventing or treating thromboembolic disorders.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), syntheticpentasaccharides, and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®).

Current anti-platelet therapies have limitations including increasedrisk of bleeding as well as partial efficacy (relative cardiovascularrisk reduction in the 20 to 30% range). Thus, discovering and developingsafe and efficacious oral or parenteral antithrombotics for theprevention and treatment of a wide range of thromboembolic disordersremains an important goal.

Alpha-thrombin is the most potent known activator of plateletaggregation and degranulation. Activation of platelets is causallyinvolved in atherothrombotic vascular occlusions. Thrombin activatesplatelets by cleaving G-protein coupled receptors termed proteaseactivated receptors (PARs). PARs provide their own cryptic ligandpresent in the N-terminal extracellular domain that is unmasked byproteolytic cleavage, with subsequent intramolecular binding to thereceptor to induce signaling (tethered ligand mechanism; Coughlin, S.R., Nature, 407:258-264 (2000)). Synthetic peptides that mimic thesequence of the newly formed N-terminus upon proteolytic activation caninduce signaling independent of receptor cleavage. Platelets are a keyplayer in atherothrombotic events. Human platelets express at least twothrombin receptors, commonly referred to as PAR1 and PAR4. Inhibitors ofPAR1 have been investigated extensively, and several compounds,including vorapaxar and atopaxar have advanced into late stage clinicaltrials. Recently, in the TRACER phase III trial in ACS patients,vorapaxar did not significantly reduce cardiovascular events, butsignificantly increased the risk of major bleeding (Tricoci, P. et al.,N. Eng. J. Med., 366(1):20-33 (2012). Thus, there remains a need todiscover new antiplatelet agents with increased efficacy and reducedbleeding side effects.

There are several early reports of preclinical studies of PAR4inhibitors. Lee, F-Y. et al., “Synthesis of1-Benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole Analogues as NovelAntiplatelet Agents”, J. Med. Chem., 4-(((22):3746-3749 (2001) disclosesin the abstract that the compound

“was found to be a selective and potent inhibitor or protease-activatedreceptor type 4 (PAR4)-dependent platelet activation.” Compound 58 isalso referred to as YD-3 in Wu, C-C. et al., “Selective Inhibition ofProtease-activated Receptor 4-dependent Platelet Activation by YD-3”,Thromb. Haemost., 87:1026-1033 (2002). Also, see Chen, H. S. et al.,“Synthesis and antiplatelet activity of ethyl4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives”, Bioorg. Med.Chem., 16:1262-1278 (2008).

EP1166785 A1 and EP0667345 disclose various pyrazole derivatives whichare useful as inhibitors of platelet aggregation.

The PCT publications WO 2013/163279, WO 2013/163244, and WO 2013/163241disclose various PAR4 antagonists that are useful as inhibitors ofplatelet aggregation.

There still remains a need for compounds useful as inhibitors ofplatelet aggregation.

Applicants have found potent compounds that have activity as PAR4inhibitors. These compounds are provided to be useful as pharmaceuticalswith desirable potency, stability, bioavailability, therapeutic index,and toxicity values that are important to their drugability.

SUMMARY OF THE INVENTION

It has been found that bicyclic heteroaryl substituted compounds inaccordance with the present invention are PAR4 antagonists which inhibitplatelet aggregation in gamma-thrombin induced platelet aggregationassays.

Accordingly, the present invention provides bicyclic heteroarylsubstituted compounds that are PAR4 antagonists and are useful asselective inhibitors of platelet aggregation, including stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof. The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for the treatment orprophylaxis of thromboembolic disorders comprising administering to apatient in need of such treatment or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for the manufacture ofa medicament for the treatment or prophylaxis of a thromboembolicdisorder.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION

The first aspect of the present invention provides at least one compoundof Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII):

or a salt thereof; wherein

R₁ is F, Cl, —OH, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ fluorocycloalkyl, C₁₋₄ alkoxy, C₁₋₄fluoroalkoxy, C₂₋₄ hydroxyalkoxy, C₃₋₆ cycloalkoxy, (C₁₋₃ alkoxy)-(C₁₋₃alkylene), (C₁₋₃ alkoxy)-(C₁₋₃ fluoroalkylene), (C₁₋₃deuteroalkoxy)-(C₁₋₃ deuteroalkylene), (C₁₋₃ fluoroalkoxy)-(C₁₋₃alkylene), (C₁₋₃ fluoroalkoxy)-(C₁₋₃ fluoroalkylene),—(CH₂)₁₋₃O(phenyl), —(CH₂)₁₋₃ NR_(a)R_(a), —C(O)O(C₁₋₆ alkyl),—C(O)NR_(a)R_(a), —C(O)NR_(b)R_(b), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)₂, —NH(C₁₋₆ hydroxyalkyl), azetidinyl, pyrrolidinyl, furanyl,pyranyl, piperidinyl, morpholinyl, piperazinyl, —S(O)₂(C₁₋₃ alkyl),—S(O)₂NR_(a)R_(a), C₁₋₃ alkylthio, or C₁₋₃ fluoroalkylthio;

R₂, at each occurrence, is independently H, F, Cl, Br, —OH, —CN, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃ aminoalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ fluorocycloalkyl, C₁₋₆alkoxy, C₁₋₃ fluoroalkoxy, C₁₋₃ alkylthio, C₁₋₃ fluoroalkylthio, (C₁₋₃alkoxy)-(C₁₋₃ alkylene), (C₁₋₃ fluoroalkoxy)-(C₁₋₃ alkylene), —C(O)NH₂,—C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ alkyl)₂, —C(O)O(C₁₋₆ alkyl),—C(O)NH(CH₂CH₂O(C₁₋₃ alkyl)), —C(O)NR_(b)R_(b), —C(O)(piperidinyl),—CH(OH)(C₃₋₆ cycloalkyl), —CH(OH)(phenyl), —CH(OH)(pyridyl), —S(O)₂(C₁₋₃alkyl), —S(O)₂NR_(a)R_(a), or a cyclic group selected from phenyl, 5- to6-membered heteroaryl, and 5- to 7-membered heterocyclyl, wherein saidcyclic group is substituted with zero to 5 substituents independentlyselected from F, Cl, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, cyclopropyl, and—CN;

R₃ is a bicyclic group selected from indolyl, benzofuranyl,benzo[b]thiophenyl, benzo[d]imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, imidazol[1,2-a]pyridinyl, thiazolo[4,5-b]pyridinyl,thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl,thiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl,4,5,6,7-tetrahydrobenzofuranyl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl,5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl,5,6-dihydro-4H-cyclopenta[d]thiazolyl, indolizinyl,pyrrolo[1,2-a]pyrimidinyl, 6,7-dihydrothiazolo[5,4-c]pyridinyl,6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazinyl,4,5,6,7-tetrahydrobenzothiophenyl, furo[3,2-b]pyridinyl, andfuro[2,3-b]pyridinyl, each bicyclic group substituted with zero to 3R_(3a);

R_(3a), at each occurrence, is independently:

(i) F, Cl, —CN, —OH, C₁₋₃ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ hydroxyalkyl,C₁₋₆ hydroxy-deuteroalkyl, C₁₋₆ hydroxy-fluoroalkyl, C₁₋₆ alkoxy, C₁₋₃fluoroalkoxy, C₃₋₆ cycloalkyl, C₃₋₆ fluorocycloalkyl, 4- to 7-memberedheterocyclyl, —CH(OH)R_(y) wherein R_(y) is C₃₋₆ cycloalkyl, aryl,heteroaryl, or 4- to 7-membered heterocyclyl; (C₁₋₃ alkoxy)-(C₁₋₃alkylene), —(CH₂)₁₋₃NR_(a)R_(a), —(CH₂)₁₋₃ NHS(O)₂(aryl), —O(CH₂)₁₋₃(aryl), —O(CH₂)₁₋₃ (thiazolyl), —O(CH₂)₁₋₃ (oxazolidinonyl), —O(CH₂)₁₋₃(amino isoxazolyl), —O(CH₂)₁₋₃ (imidazolyl substituted with phenyl),C₁₋₆ hydroxyalkoxy, (C₁₋₃ alkoxy)-(C₁₋₆ alkoxy), —O(CH₂)₁₋₄O(aryl),—O(CH₂)₁₋₄O(CH₂)₁₋₃ (aryl), —O(CH₂)₁₋₄NR_(a)R_(a),—O(CH₂)₁₋₃CHR_(a)NR_(a)(methoxy pyrimidinyl), —O(CH₂)₁₋₄ NHS(O)₂(C₁₋₃alkyl), —O(CH₂)₁₋₄ NHS(O)₂(aryl), —O(CH₂)₁₋₄C(O)OH, —O(CH₂)₁₋₄C(O)O(C₁₋₆alkyl), —O(CH₂)₁₋₄C(O)NR_(a)(CH₂)₀₋₃ (aryl),—O(CH₂)₁₋₄C(O)NR_(a)(CH₂)₀₋₃ (heteroaryl), —O(CH₂)₁₋₄C(O)(morpholinyl),—O(CH₂)₁₋₄OC(O)O(C₁₋₃ alkyl), —O(CH₂)₁₋₃CHR_(a)OC(O)NR_(a)(CH₂)₁₋₄C(O)NR_(a)R_(a),—CH₂CHR_(d)OC(O)NR_(a)(heteroaryl), —O(CH₂)₁₋₄OC(O)NR_(a)(heteroaryl),—O(imidazolyl substituted with aryl), —C(O)OH, —C(O)O(C₁₋₆ alkyl),—NR_(a)C(O)(furanyl), —NR_(a)C(O)(pyranyl), —NR_(a)C(O)O(C₁₋₆ alkyl),—NR_(a)C(O)O(CH₂)₁₋₄(aryl), —O(CH₂)₁₋₄NR_(a)C(O)O(C₁₋₆ alkyl),—O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄(tetrahydropyranyl),—O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄(aryl),—O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄(heteroaryl), or—O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄(tetrahydrofuranyl), wherein each of saidaryl, heteroaryl, and 3- to 6-membered heterocyclyl is substituted withzero to 5 substituents independently selected from F, Cl, —CN, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃ alkoxy, —OCF₃, —OCHF₂,—NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C(O)O(C₁₋₃ alkyl), C₁₋₃hydroxyalkoxy, phenyl, —CONR_(c)R_(c), and —S(O)₂NR_(c)R_(c);(ii) —CH(OH)CR_(h)R_(i)R_(j) wherein R_(h) and R_(i) are independentlyH, F, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, ortaken together with the carbon atom to which they are attached, formC₃₋₈ cycloalkyl or 4- to 7-membered heterocyclyl ring; and R_(j) is H,C₁₋₆ alkyl, C₁₋₅ fluoroalkyl, (C₁₋₃ alkoxy)-(C₁₋₃ alkylene), C₃₋₈cycloalkyl, C₃₋₈ heterocyclyl, aryl, or heteroaryl;(iii) —O(CH₂)₁₋₄NR_(a)S(O)₂(C₁₋₄ alkyl) or —O(CH₂)₁₋₄NR_(a)S(O)₂R_(w),wherein R_(w) is aryl or heteroaryl, each substituted with zero to 2substituents independently selected from F, Cl, cyano, C₁₋₃ alkyl, C₁₋₃alkoxy, —OCF₃, —OCHF₂, and C₁₋₃ fluoroalkyl; or(iv) —O(CH₂)₁₋₄OC(O)NR_(a)R_(x), —OCH(R_(d))(CH₂)₁₋₃OC(O)NR_(a)R_(x),—OCR_(d)R_(d)(CH₂)₁₋₃OC(O)NR_(a)R_(x), —O(CH₂)₁₋₃CH(R_(d))OC(O)NR_(a)R_(x), —O(CH₂)₁₋₃CR_(d)R_(d)OC(O)NR_(a)R_(x),—OCH(R_(d))CH(R_(d))(CH₂)₀₋₂OC(O)NR_(a)R_(x), or—OCR_(d)R_(d)CR_(d)R_(d)(CH₂)₀₋₂OC(O)NR_(a)R_(x), wherein R_(x) isselected from H, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, aryl, heteroaryl, and—CH₂(heteroaryl), each aryl and heteroaryl substituted with zero to 2substituents independently selected from F, Cl, Br, —CN, —OH, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ hydroxy-deuteroalkyl,C₁₋₆ hydroxyalkoxy, C₁₋₆ hydroxy-fluoroalkoxy, C₁₋₃ alkoxy, —C(O)OH,—(CH₂)₀₋₃C(O)O(C₁₋₃ alkyl), —(CH₂)₁₋₃OP(O)(OH)₂, —CH₂(morpholinyl),—C(O)NH₂, —C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ alkyl)₂, —C(O)NR_(a)(C₁₋₆hydroxyalkyl), —C(O)NR_(b)R_(b), —S(O)₂NR_(a)R_(a), —NH₂, —NH(C₁₋₆alkyl), —NR_(a)(C₁₋₆ hydroxyalkyl), —N(C₁₋₆ alkyl)₂, —NR_(a)C(O)(C₁₋₆alkyl), —NR_(a)C(O)(chloro, fluorophenyl), —NR_(a)S(O)₂(C₁₋₃ alkyl),—C(O)NR_(a)(CH₂)₀₋₁(hydroxymethyloxetanyl), —C(O)NR_(a)(CH₂)₀₋₁(hydroxymethyl C₃₋₆ cycloalkyl), —C(O)NR_(a)(CH₂)₀₋₁(hydroxy C₃₋₆cycloalkyl), —C(O)NHCH₂C(CH₃)₂OP(O)(OH)₂, —C(O)(hydroxypiperidinyl),—C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl),—C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), pyrrolidinyl,morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl;

R₄ is H, F, Cl, or —CH₃;

R_(a), at each occurrence, is independently H, C₁₋₄alkyl, or C₁₋₄fluoroalkyl;

two R_(b) along with the nitrogen atom to which they are attached form a4- to 7-membered heterocyclo ring having 1 to 2 nitrogen atoms and 0-1oxygen or sulfur atoms;

R_(c), at each occurrence, is independently C₁₋₃ alkyl or C₁₋₃hydroxyalkyl, or two R_(c) along with the nitrogen atom to which theyare attached form a heterocyclyl or bicyclic heterocyclyl;

R_(d), at each occurrence, is independently C₁₋₆ alkyl, C₁₋₄fluoroalkyl, C₁₋₆ hydroxyalkyl, (C₁₋₄ alkoxy)-(C₁₋₃ alkylene), (C₁₋₂fluoroalkoxy)-(C₁₋₂ alkylene), (C₃₋₆ cycloalkyl)-(C₀₋₂ alkylene),aryl(C₁₋₂ alkylene), heteroaryl(C₁₋₂ alkylene), aryloxy-(C₁₋₂ alkylene),aryl-CH₂O—(C₁₋₂ alkylene), or heteroaryloxy-(C₁₋₂ alkylene); and

n is zero, 1, or 2.

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein

R₁ is —OH, C₁₋₂ alkyl, —CHFCH₃, —CH═CH₂, C₁₋₃ alkoxy, C₁₋₂ fluoroalkoxy,—OCH₂CH₂OH, —CH₂O(C₁₋₂ alkyl), —CD₂OCD₃, —CH₂OCHF₂, —CF₂OCH₃,—CH₂O(phenyl), —CH(CH₃)OCH₃, —NH(CH₃), —N(CH₃)₂, —CH₂N(CH₃)₂, —C(O)NH₂,—C(O)NH(CH₃), —C(O)N(CH₃)₂, —C(O)NH(CH₂CH₂OH), —C(O)OCH₃, —CH(CH₃)OCH₃,cyclopropyl, furanyl, or —O(cyclopropyl);

R₂, at each occurrence, is independently H, F, Cl, —CN, —CH₃, —CH₂F,—CHF₂, —CF₃, —OCH₃, —OCF₃, —CH₂OH, —CH₂CH₂OH, —CH(CH₃)OH, —C(CH₃)₂OH,—CH(OH)CH₂OH, —CH₂NH₂, —C(O)NH₂, —C(O)N(CH₃)₂, —C(O)(piperidinyl),—C(O)OCH₃, —C(O)NH(CH₂CH₂OCH₃), —CH(OH)(cyclopropyl), —CH(OH)(phenyl),—CH═CH₂, —C(CH₃)═CH₂, or —C≡CH;

R₃ is:

R_(3a), at each occurrence, is independently:

-   (i) F, Cl, —CN, —OH, —CH₃, —CF₃, —CHFC(CH₃)₃, cyclopropyl, —CH₂OH,    —CD₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —C(CH₃)₂OH, —CH(OH)C(CH₃)₃,    —CD(OH)C(CH₃)₃, —CH(OH)CF₃, —CH(OH)CH₂CF₃, —CH(OH)(cyclopropyl),    —CH(OH)(methylcyclopropyl), —CH(OH)(trifluoromethylcyclopropyl),    —CH(OH)(cyclopropyl substituted with phenyl), —CH(OH)(cyclobutyl),    —CH(OH)(methoxycyclobutyl), —CH(OH)(ethoxycarbonylcyclobutyl),    —CH(OH)(trifluoromethylcyclobutyl),    —CH(OH)(hydroxymethylcyclobutyl), —CH(OH)(cyclobutyl substituted    with phenyl), —CH(OH)(cyclohexyl), —CH(OH)(methylcyclohexyl),    —CH(OH)(phenyl), —CH(OH)(isopropylphenyl),    —CH(OH)(trifluoromethylphenyl), —CH(OH)(fluoro, methoxyphenyl),    —CH(OH)(pyridinyl), —CH(OH)(thiazolyl), —CH(OH)(tetrahydropyranyl),    —CH(OH)(methyltetrahydropyranyl), —CH₂OCH₃, —CH₂N(CH₃)₂,    —CH₂NHS(O)₂(phenyl), or —CH(OH)CH₂(phenyl);-   (ii) —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —OCF₃, —OCHF₂, —OCH₂(phenyl),    —OCH₂(thiazolyl), —OCH₂(oxazolidinonyl), —OCH₂(amino isoxazolyl),    —OCH₂(imidazolyl substituted with phenyl), —OCH₂CH₂OH,    —OCH₂CH(CH₃)OH, —OCH₂CH₂OCH₃, —OCH(CH₃)CH₂OH, —OCH₂CH(OH)CH₃,    —OCH(CH₃)CH(OH)CH₃, —OCH₂C(CH₃)₂OH, —OCH₂CH₂O(phenyl),    —OCH₂CH₂OCH₂(phenyl), —OCH₂CH₂NH(CH₃), —OCH₂CH(CH₃)NH(methoxy    pyrimidinyl), —OCH₂C(O)OH, —OCH₂C(O)OCH₃, —OCH₂C(O)OCH₂CH₃,    —OCH₂C(O)OC(CH₃)₃, —OCH₂C(O)NH(phenyl), —OCH₂C(O)NHCH₂(phenyl),    —OCH₂C(O)(morpholinyl), —OCH₂CH₂CH₂C(O)NH(pyridinyl),    —OCH₂CH₂OC(O)OCH₃, —OCH₂CH(CH₃)OC(O)NHCH₂CH₂C(O)NH₂,    —OCH₂CH(CH₂CH₃)OC(O)NH(pyridinyl),    —OCH₂CH(CH₂OCH₃)OC(O)NH(pyridinyl),    —OCH₂CH(CH₂OC(CH₃)₃)OC(O)NH(pyridinyl),    —OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(pyridinyl),    —OCH₂CH(CH₂OCH₂(phenyl))OC(O)NH(pyridinyl),    —OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(pyrimidinyl), or    —OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(methyl pyrimidinyl);-   (iii) —C(O)OH, —C(O)OCH₃, or —C(O)OC(CH₃)₃;-   (iv) —NHC(O)OCH₃, —NHC(O)OC(CH₃)₃, —NHC(O)OCH₂(phenyl),    —NHC(O)OCH₂(tetrahydrofuranyl), or —NHC(O)O(tetrahydropyranyl);-   (v) —OCH₂CH₂NHC(O)OCH₃, —OCH₂CH₂NHC(O)O(tetrahydropyranyl),    —OCH₂CH₂NHC(O)OCH₂(phenyl), —OCH₂CH₂NHC(O)O(methoxyphenyl),    —OCH₂CH₂NHC(O)O(tetrahydrofuranyl),    —OCH₂CH₂NHC(O)OCH₂(tetrahydrofuranyl), —OCH₂CH₂NHC(O)NH(pyridinyl),    —OCH₂CH₂N(CH₃)C(O)NH(methylpyrimidinyl), or    —OCH₂CH(CH₃)OC(O)OCH₂(aminopyridinyl);-   (vi) —OCH₂CH₂NHS(O)₂CH₃ or —OCH₂CH₂NHS(O)₂R_(w) wherein R_(w) is    phenyl or pyridinyl, each substituted with zero to 2 substituents    independently selected from F, Cl, and —CH₃; or-   (vii) —OCH₂CH₂OC(O)NHR_(z), —OCH(CH₃)CH₂OC(O)NHR_(z),    —OCH₂CH(CH₃)OC(O)NHR_(z), —OCH(CH₃)CH(CH₃)OC(O)NHR_(z),    —OCH₂CH(CH₂O(isobutyl))OC(O)NHR_(z), —OCH₂CH(CH₂CH₃)OC(O)NHR_(z),    —OCH₂CH(CH₂OCH₃)OC(O)NHR_(z), or    —OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NHR_(z)    wherein R_(z) is H, —CH₂CF₃, phenyl, pyrrolyl, pyrazolyl, thiazolyl,    isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,    oxadiazolyl, thiadiazolyl, indolyl, pyrrolo[2,3-b]pyridinyl,    benzo[d]oxazolonyl, —CH₂(pyrazolyl), —CH₂(imidazolyl), or    —CH₂(pyridinyl), each substituted with zero to 2 substituents    independently selected from F, Cl, Br, —CN, —OH, —CH₃, —CH₂CH₂CH₃,    —CF₃, —CH₂OH, —CD₂OH, —CH(CH₃)OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,    —C(CH₃)₂OH, —CH₂CH(CH₃)OH, —CH₂C(CH₃)₂OH, —CH₂CH₂C(O)OCH₃,    —CH₂OP(O)(OH)₂, —CH₂CH₂OP(O)(OH)₂, —CH₂(morpholinyl), —OCH₃,    —OCH₂CH₂OH, —OCH₂CH(CH₃)OH, —OCH₂C(CH₃)₂OH, —OCH₂CH₂C(CH₃)₂OH,    —OCH(CH₃)CH₂OH, —OCH₂CH(OH)CH₂OH, —OCH₂CF₂OH, —OCH₂CF₂CH₂OH,    —C(O)OH, —C(O)OCH₃, —C(O)NH₂, —C(O)NH(CH₃), —C(O)N(CH₃)₂,    —C(O)NH(CH₂CH₂OH), —C(O)NH(CH₂CH(CH₃)OH), —C(O)NH(CH₂C(CH₃)₂OH),    —C(O)NH(CH₂C(CH₃)₂CH₂OH), —C(O)NH(CH₂CH₂C(CH₃)₂OH),    —C(O)N(CH₃)CH₂CH₂OH, —C(O)N(CH₃)CH₂C(CH₃)₂OH,    —C(O)NHCH₂(hydroxymethyloxetanyl), —C(O)NH(hydroxymethylcyclobutyl),    —C(O)NHCH₂(hydroxycyclobutyl), —C(O)NHCH₂(hydroxymethylcyclobutyl),    —C(O)NHCH₂C(CH₃)₂OP(O)(OH)₂, —C(O)(hydroxypiperidinyl),    —C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl),    —C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), —NH₂, —N(CH₃)₂,    —NHC(O)CH₃, —NHC(O)(chloro, fluorophenyl), —NH(CH₂C(CH₃)₂OH),    —N(CH₃)S(O)₂CH₃, pyrrolidinyl, morpholinyl, thiophenyl, methyl    triazolyl, and oxazolidinonyl;    R₄ is H, F, or —CH₃; and    p is zero, 1, 2, or 3.

One embodiment provides at least one compound of Formulas (I), (II),(III) or (IV) or a salt thereof, wherein R₁, R₂, R₃, R₄, and n aredefined in the first aspect. Included in this embodiment are compoundsin which R₃ is:

p is zero, 1, 2, or 3; and R_(3a) is defined in the first aspect. Alsoincluded in this embodiment are compounds in which R₄ is H, F, or —CH₃.

One embodiment provides at least one compound of Formulas (I), (II),(III), or (IV) or a salt thereof, wherein R₁, R₂, R₃, R₄, and n aredefined in the first aspect.

One embodiment provides at least one compound of Formulas (I) or (II) ora salt thereof, wherein R₁, R₂, R₃, R₄, and n are defined in the firstaspect.

One embodiment provides at least one compound of Formula (I) or a saltthereof, wherein R₁, R₂, R₃, R₄, and n are defined in the first aspect.

One embodiment provides at least one compound of Formula (II) or a saltthereof, wherein R₁, R₂, R₃, R₄, and n are defined in the first aspect.

One embodiment provides at least one compound of Formula (III) or a saltthereof, wherein R₁, R₂, R₃, and n are defined in the first aspect.

One embodiment provides at least one compound of Formula (IV) or a saltthereof, wherein R₁, R₂, R₃, and n are defined in the first aspect.

One embodiment provides at least one compound of Formula (V) or a saltthereof, wherein R₁, R₂, R₃, R₄, and n are defined in the first aspect.

One embodiment provides at least one compound of Formula (VI) or a saltthereof, wherein R₁, R₂, R₃, and n are defined in the first aspect.

One embodiment provides at least one compound of Formula (VII) or a saltthereof, wherein R₁, R₂, R₃, R₄, and n are defined in the first aspect.

One embodiment provides at least one compound of Formula (VIII) or asalt thereof, wherein R₁, R₂, R₃, and n are defined in the first aspect.

One embodiment provides at least one compound of Formula (I) or a saltthereof, wherein R₁, R₂, R₃, R₄, and n are defined in the first aspect.Included in this embodiment are compounds in which R₃ is:

p is zero, 1, 2, or 3; and R_(3a) is defined in the first aspect. Alsoincluded in this embodiment are compounds in which R₄ is H, F, or —CH₃.

One embodiment provides at least one compound of Formulas (I) or (II) ora salt thereof, wherein R₁, R₂, R₃, R₄, and n are defined in the firstaspect. Included in this embodiment are compounds in which R₃ is:

p is zero, 1, 2, or 3; and R_(3a) is defined in the first aspect.

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), or (VIII) or a salt thereof, wherein R₃ is:

R_(m) is H or Cl; R_(k) is H or F; and R₁, R₂, R_(3a), R₄, and n aredefined in the first aspect. Included in this embodiment are compoundsof Formula (I).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₃is:

and R₁, R₂, R_(3a), R₄, and n are defined in the first aspect. Includedin this embodiment are compounds of Formula (I).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁is —OH, C₁₋₂ alkyl, —CHFCH₃, —CH═CH₂, C₁₋₃ alkoxy, C₁₋₂ fluoroalkoxy,—OCH₂CH₂OH, —CH₂O(C₁₋₂ alkyl), —CD₂OCD₃, —CH₂OCHF₂, —CF₂OCH₃,—CH₂O(phenyl), —CH(CH₃)OCH₃, —NH(CH₃), —N(CH₃)₂, —CH₂N(CH₃)₂, —C(O)NH₂,—C(O)NH(CH₃), —C(O)N(CH₃)₂, —C(O)NH(CH₂CH₂OH), —C(O)OCH₃, —CH(CH₃)OCH₃,cyclopropyl, furanyl, or —O(cyclopropyl); and R₂, R₃, R₄, and n aredefined in the first aspect. Included in this embodiment are compoundsin which R₁ is —CH₂OCH₃, —OCH₃, or —OCHF₂.

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₂,at each occurrence, is independently H, F, Cl, —CN, —CH₃, —CH₂F, —CHF₂,—CF₃, —OCH₃, —OCF₃, —CH₂OH, —CH₂CH₂OH, —CH(CH₃)OH, —C(CH₃)₂OH,—CH(OH)CH₂OH, —CH₂NH₂, —C(O)NH₂, —C(O)N(CH₃)₂, —C(O)(piperidinyl),—C(O)OCH₃, —C(O)NH(CH₂CH₂OCH₃), —CH(OH)(cyclopropyl), —CH(OH)(phenyl),—CH═CH₂, —C(CH₃)═CH₂, or —C≡CH; and R₁, R₃, R₄, and n are defined in thefirst aspect. Included in this embodiment are compounds in which R₂ isF, Cl, —CN, —CH₃, or —CH₂OH. Also included in this embodiment arecompounds in which R₂ is —CH₃.

One embodiment provides at least one compound of Formula (I), (II), (V),and (VII) or a salt thereof, wherein R₄ is H, F, or —CH₃; and R₁, R₂,R₃, and n are defined in the first aspect. Included in this embodimentare compounds in which R₄ is H and F. Also included in this compounds inwhich R₄ is H.

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, whereinR_(3a), at each occurrence, is independently, (i) F, Cl, —CN, —OH, —CH₃,—CF₃, —CHFC(CH₃)₃, cyclopropyl, —CH₂OH, —CD₂OH, —CH₂CH₂OH, —CH(OH)CH₃,—C(CH₃)₂OH, —CH(OH)C(CH₃)₃, —CD(OH)C(CH₃)₃, —CH(OH)CF₃, —CH(OH)CH₂CF₃,—CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl),—CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl substitutedwith phenyl), —CH(OH)(cyclobutyl), —CH(OH)(methoxycyclobutyl),—CH(OH)(ethoxycarbonylcyclobutyl), —CH(OH)(trifluoromethylcyclobutyl),—CH(OH)(hydroxymethylcyclobutyl), —CH(OH)(cyclobutyl substituted withphenyl), —CH(OH)(cyclohexyl), —CH(OH)(methylcyclohexyl),—CH(OH)(phenyl), —CH(OH)(isopropylphenyl),—CH(OH)(trifluoromethylphenyl), —CH(OH)(fluoro, methoxyphenyl),—CH(OH)(pyridinyl), —CH(OH)(thiazolyl), —CH(OH)(tetrahydropyranyl),—CH(OH)(methyltetrahydropyranyl), —CH₂OCH₃, —CH₂N(CH₃)₂,—CH₂NHS(O)₂(phenyl), or —CH(OH)CH₂(phenyl); (ii) —OCH₃, —OCH₂CH₃,—OCH(CH₃)₂, —OCF₃, —OCHF₂, —OCH₂(phenyl), —OCH₂(thiazolyl),—OCH₂(oxazolidinonyl), —OCH₂(amino isoxazolyl), —OCH₂(imidazolylsubstituted with phenyl), —OCH₂CH₂OH, —OCH₂CH(CH₃)OH, —OCH₂CH₂OCH₃,—OCH(CH₃)CH₂OH, —OCH₂CH(OH)CH₃, —OCH(CH₃)CH(OH)CH₃, —OCH₂C(CH₃)₂OH,—OCH₂CH₂O(phenyl), —OCH₂CH₂OCH₂(phenyl), —OCH₂CH₂NH(CH₃),—OCH₂CH(CH₃)NH(methoxy pyrimidinyl), —OCH₂C(O)OH, —OCH₂C(O)OCH₃,—OCH₂C(O)OCH₂CH₃, —OCH₂C(O)OC(CH₃)₃, —OCH₂C(O)NH(phenyl),—OCH₂C(O)NHCH₂(phenyl), —OCH₂C(O)(morpholinyl),—OCH₂CH₂CH₂C(O)NH(pyridinyl), —OCH₂CH₂OC(O)OCH₃,—OCH₂CH(CH₃)OC(O)NHCH₂CH₂C(O)NH₂, —OCH₂CH(CH₂CH₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OC(CH₃)₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂(phenyl))OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(pyrimidinyl), or—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(methyl pyrimidinyl); (iii) —C(O)OH,—C(O)OCH₃, or —C(O)OC(CH₃)₃; (iv) —NHC(O)OCH₃, —NHC(O)OC(CH₃)₃,—NHC(O)OCH₂(phenyl), —NHC(O)OCH₂(tetrahydrofuranyl), or—NHC(O)O(tetrahydropyranyl); (v) —OCH₂CH₂NHC(O)OCH₃,—OCH₂CH₂NHC(O)O(tetrahydropyranyl), —OCH₂CH₂NHC(O)OCH₂(phenyl),—OCH₂CH₂NHC(O)O(methoxyphenyl), —OCH₂CH₂NHC(O)O(tetrahydrofuranyl),—OCH₂CH₂NHC(O)OCH₂(tetrahydrofuranyl), —OCH₂CH₂NHC(O)NH(pyridinyl),—OCH₂CH₂N(CH₃)C(O)NH(methylpyrimidinyl), or—OCH₂CH(CH₃)OC(O)OCH₂(aminopyridinyl); (vi) —OCH₂CH₂NHS(O)₂CH₃ or—OCH₂CH₂NHS(O)₂R_(w) wherein R_(w) is phenyl or pyridinyl, eachsubstituted with zero to 2 substituents independently selected from F,Cl, and —CH₃; or (vii) —OCH₂CH₂OC(O)NHR_(z), —OCH(CH₃)CH₂OC(O)NHR_(z),—OCH₂CH(CH₃)OC(O)NHR_(z), —OCH(CH₃)CH(CH₃)(CH₂)₀₋₂OC(O)NHR_(z),—OCH₂CH(CH₂O(isobutyl))(CH₂)₀₋₂OC(O)NHR_(z),—OCH₂CH(CH₂CH₃)OC(O)NHR_(z), —OCH₂CH(CH₂OCH₃)OC(O)NHR_(z), or—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NHR_(z) wherein R_(z) is H, —CH₂CF₃,phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, —CH₂(pyrazolyl),—CH₂(imidazolyl), or —CH₂(pyridinyl), each substituted with zero to 2substituents independently selected from F, Cl, Br, —CN, —OH, —CH₃,—CH₂CH₂CH₃, —CF₃, —CH₂OH, —CD₂OH, —CH(CH₃)OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—C(CH₃)₂OH, —CH₂CH(CH₃)OH, —CH₂C(CH₃)₂OH, —CH₂CH₂C(O)OCH₃,—CH₂OP(O)(OH)₂, —CH₂CH₂OP(O)(OH)₂, —CH₂(morpholinyl), —OCH₃, —OCH₂CH₂OH,—OCH₂CH(CH₃)OH, —OCH₂C(CH₃)₂OH, —OCH₂CH₂C(CH₃)₂OH, —OCH(CH₃)CH₂OH,—OCH₂CH(OH)CH₂OH, —OCH₂CF₂OH, —OCH₂CF₂CH₂OH, —C(O)OH, —C(O)OCH₃,—C(O)NH₂, —C(O)NH(CH₃), —C(O)N(CH₃)₂, —C(O)NH(CH₂CH₂OH),—C(O)NH(CH₂CH(CH₃)OH), —C(O)NH(CH₂C(CH₃)₂OH), —C(O)NH(CH₂C(CH₃)₂CH₂OH),—C(O)NH(CH₂CH₂C(CH₃)₂OH), —C(O)N(CH₃)CH₂CH₂OH, —C(O)N(CH₃)CH₂C(CH₃)₂OH,—C(O)NHCH₂(hydroxymethyloxetanyl), —C(O)NH(hydroxymethylcyclobutyl),—C(O)NHCH₂(hydroxycyclobutyl), —C(O)NHCH₂(hydroxymethylcyclobutyl),—C(O)NHCH₂C(CH₃)₂OP(O)(OH)₂, —C(O)(hydroxypiperidinyl),—C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl),—C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), —NH₂, —N(CH₃)₂,—NHC(O)CH₃, —NHC(O)(chloro, fluorophenyl), —NH(CH₂C(CH₃)₂OH),—N(CH₃)S(O)₂CH₃, pyrrolidinyl, morpholinyl, thiophenyl, methyltriazolyl, and oxazolidinonyl; and R₁, R₂, R₃, R₄, and n are defined inthe first aspect.

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₃is substituted with one R_(3a) selected from (i) F, Cl, —CN, —OH, —CH₃,—CF₃, —CHFC(CH₃)₃, cyclopropyl, —CH₂OH, —CD₂OH, —CH₂CH₂OH, —CH(OH)CH₃,—C(CH₃)₂OH, —CH(OH)C(CH₃)₃, —CD(OH)C(CH₃)₃, —CH(OH)CF₃, —CH(OH)CH₂CF₃,—CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl),—CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl substitutedwith phenyl), —CH(OH)(cyclobutyl), —CH(OH)(methoxycyclobutyl),—CH(OH)(ethoxycarbonylcyclobutyl), —CH(OH)(trifluoromethylcyclobutyl),—CH(OH)(hydroxymethylcyclobutyl), —CH(OH)(cyclobutyl substituted withphenyl), —CH(OH)(cyclohexyl), —CH(OH)(methylcyclohexyl),—CH(OH)(phenyl), —CH(OH)(isopropylphenyl),—CH(OH)(trifluoromethylphenyl), —CH(OH)(fluoro, methoxyphenyl),—CH(OH)(pyridinyl), —CH(OH)(thiazolyl), —CH(OH)(tetrahydropyranyl),—CH(OH)(methyltetrahydropyranyl), —CH₂OCH₃, —CH₂N(CH₃)₂,—CH₂NHS(O)₂(phenyl), or —CH(OH)CH₂(phenyl); (ii) —OCH₃, —OCH₂CH₃,—OCH(CH₃)₂, —OCF₃, —OCHF₂, —OCH₂(phenyl), —OCH₂(thiazolyl),—OCH₂(oxazolidinonyl), —OCH₂(amino isoxazolyl), —OCH₂(imidazolylsubstituted with phenyl), —OCH₂CH₂OH, —OCH₂CH(CH₃)OH, —OCH₂CH₂OCH₃,—OCH(CH₃)CH₂OH, —OCH₂CH(OH)CH₃, —OCH(CH₃)CH(OH)CH₃, —OCH₂C(CH₃)₂OH,—OCH₂CH₂O(phenyl), —OCH₂CH₂OCH₂(phenyl), —OCH₂CH₂NH(CH₃),—OCH₂CH(CH₃)NH(methoxy pyrimidinyl), —OCH₂C(O)OH, —OCH₂C(O)OCH₃,—OCH₂C(O)OCH₂CH₃, —OCH₂C(O)OC(CH₃)₃, —OCH₂C(O)NH(phenyl),—OCH₂C(O)NHCH₂(phenyl), —OCH₂C(O)(morpholinyl),—OCH₂CH₂CH₂C(O)NH(pyridinyl), —OCH₂CH₂OC(O)OCH₃,—OCH₂CH(CH₃)OC(O)NHCH₂CH₂C(O)NH₂, —OCH₂CH(CH₂CH₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OC(CH₃)₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂(phenyl))OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(pyrimidinyl), or—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(methyl pyrimidinyl); (iii) —C(O)OH,—C(O)OCH₃, or —C(O)OC(CH₃)₃; (iv) —NHC(O)OCH₃, —NHC(O)OC(CH₃)₃,—NHC(O)OCH₂(phenyl), —NHC(O)OCH₂(tetrahydrofuranyl), or—NHC(O)O(tetrahydropyranyl); (v) —OCH₂CH₂NHC(O)OCH₃,—OCH₂CH₂NHC(O)O(tetrahydropyranyl), —OCH₂CH₂NHC(O)OCH₂(phenyl),—OCH₂CH₂NHC(O)O(methoxyphenyl), —OCH₂CH₂NHC(O)O(tetrahydrofuranyl),—OCH₂CH₂NHC(O)OCH₂(tetrahydrofuranyl), —OCH₂CH₂NHC(O)NH(pyridinyl),—OCH₂CH₂N(CH₃)C(O)NH(methylpyrimidinyl), or—OCH₂CH(CH₃)OC(O)OCH₂(aminopyridinyl); (vi) —OCH₂CH₂NHS(O)₂CH₃ or—OCH₂CH₂NHS(O)₂R_(w) wherein R_(w) is phenyl or pyridinyl, eachsubstituted with zero to 2 substituents independently selected from F,Cl, and —CH₃; or (vii) —OCH₂CH₂OC(O)NHR_(z), —OCH(CH₃)CH₂OC(O)NHR_(z),—OCH₂CH(CH₃)OC(O)NHR_(z), —OCH(CH₃)CH(CH₃)(CH₂)₀₋₂OC(O)NHR_(z),—OCH₂CH(CH₂O(isobutyl))(CH₂)₀₋₂OC(O)NHR_(z),—OCH₂CH(CH₂CH₃)OC(O)NHR_(z), —OCH₂CH(CH₂OCH₃)OC(O)NHR_(z), or—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NHR_(z) wherein R_(z) is H, —CH₂CF₃,phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, —CH₂(pyrazolyl),—CH₂(imidazolyl), or —CH₂(pyridinyl), each substituted with zero to 2substituents independently selected from F, Cl, Br, —CN, —OH, —CH₃,—CH₂CH₂CH₃, —CF₃, —CH₂OH, —CD₂OH, —CH(CH₃)OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—C(CH₃)₂OH, —CH₂CH(CH₃)OH, —CH₂C(CH₃)₂OH, —CH₂CH₂C(O)OCH₃,—CH₂OP(O)(OH)₂, —CH₂CH₂OP(O)(OH)₂, —CH₂(morpholinyl), —OCH₃, —OCH₂CH₂OH,—OCH₂CH(CH₃)OH, —OCH₂C(CH₃)₂OH, —OCH₂CH₂C(CH₃)₂OH, —OCH(CH₃)CH₂OH,—OCH₂CH(OH)CH₂OH, —OCH₂CF₂OH, —OCH₂CF₂CH₂OH, —C(O)OH, —C(O)OCH₃,—C(O)NH₂, —C(O)NH(CH₃), —C(O)N(CH₃)₂, —C(O)NH(CH₂CH₂OH),—C(O)NH(CH₂CH(CH₃)OH), —C(O)NH(CH₂C(CH₃)₂OH), —C(O)NH(CH₂C(CH₃)₂CH₂OH),—C(O)NH(CH₂CH₂C(CH₃)₂OH), —C(O)N(CH₃)CH₂CH₂OH, —C(O)N(CH₃)CH₂C(CH₃)₂OH,—C(O)NHCH₂(hydroxymethyloxetanyl), —C(O)NH(hydroxymethylcyclobutyl),—C(O)NHCH₂(hydroxycyclobutyl), —C(O)NHCH₂(hydroxymethylcyclobutyl),—C(O)NHCH₂C(CH₃)₂OP(O)(OH)₂, —C(O)(hydroxypiperidinyl),—C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl),—C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), —NH₂, —N(CH₃)₂,—NHC(O)CH₃, —NHC(O)(chloro, fluorophenyl), —NH(CH₂C(CH₃)₂OH),—N(CH₃)S(O)₂CH₃, pyrrolidinyl, morpholinyl, thiophenyl, methyltriazolyl, and oxazolidinonyl; and zero to 2 R_(3a) independentlyselected from F, Cl, —CN, —CH₃, —CF₃, and —OCH₃; and R₁, R₂, R₃, R₄, andn are defined in the first aspect.

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, R_(a), R_(b), R_(d), and n are defined in the firstaspect with the proviso that at least one R_(3a) is F, Cl, —CN, —OH,C₁₋₃ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆hydroxy-deuteroalkyl, C₁₋₆ hydroxy-fluoroalkyl, C₁₋₆ alkoxy, C₁₋₃fluoroalkoxy, C₃₋₆ cycloalkyl, C₃₋₆ fluorocycloalkyl, 3- to 6-memberedheterocyclyl, —CH(OH)R_(y) wherein R_(y) is C₃₋₆ cycloalkyl, aryl,heteroaryl, or 3- to 6-membered heterocyclyl; (C₁₋₃ alkoxy)-(C₁₋₃alkylene), —(CH₂)₁₋₃NR_(a)R_(a), —(CH₂)₁₋₃ NHS(O)₂(aryl), —O(CH₂)₁₋₃(aryl), —O(CH₂)₁₋₃ (thiazolyl), —O(CH₂)₁₋₃ (oxazolidinonyl), —O(CH₂)₁₋₃(amino isoxazolyl), —O(CH₂)₁₋₃ (imidazolyl substituted with phenyl),C₁₋₆ hydroxyalkoxy, (C₁₋₃ alkoxy)-(C₁₋₆ alkoxy), —O(CH₂)₁₋₄O(aryl),—O(CH₂)₁₋₄O(CH₂)₁₋₃ (aryl), —O(CH₂)₁₋₄NR_(a)R_(a),—O(CH₂)₁₋₃CHR_(a)R_(a)(methoxy pyrimidinyl), —O(CH₂)₁₋₄ NHS(O)₂(C₁₋₃alkyl), —O(CH₂)₁₋₄NHS(O)₂(aryl), —O(CH₂)₁₋₄C(O)OH, —O(CH₂)₁₋₄C(O)O(C₁₋₆alkyl), —O(CH₂)₁₋₄C(O)NR_(a)(CH₂)₀₋₃ (aryl),—O(CH₂)₁₋₄C(O)NR_(a)(CH₂)₀₋₃ (heteroaryl), —O(CH₂)₁₋₄C(O)(morpholinyl),—O(CH₂)₁₋₄OC(O)O(C₁₋₃ alkyl), —O(CH₂)₁₋₃CHR_(a)OC(O)NR_(a)(CH₂)₁₋₄C(O)NR_(a)R_(a),—CH₂CHR_(d)OC(O)NR_(a)(heteroaryl), —O(CH₂)₁₋₄OC(O)NR_(a)(heteroaryl),—O(imidazolyl substituted with aryl), —C(O)OH, —C(O)O(C₁₋₆ alkyl),—NR_(a)C(O)(furanyl), —NR_(a)C(O)(pyranyl), —NR_(a)C(O)O(C₁₋₆ alkyl),—NR_(a)C(O)O(CH₂)₁₋₄ (aryl), —O(CH₂)₁₋₄NR_(a)C(O)O(C₁₋₆ alkyl),—O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄ (tetrahydropyranyl),—O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄ (aryl), —O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄(heteroaryl), or —O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄(tetrahydrofuranyl),wherein each of said aryl, heteroaryl, and 3- to 6-membered heterocyclylis substituted with zero to 5 substituents independently selected fromF, Cl, —CN, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃alkoxy, —OCF₃, —OCHF₂, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C(O)O(C₁₋₃ alkyl), C₁₋₃ hydroxyalkoxy, phenyl, —CONR_(c)R_(c), and—S(O)₂NR_(c)R_(c).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, R_(a), R_(b), R_(d), and n are defined in the firstaspect with the proviso that at least one R_(3a) is—CH(OH)CR_(h)R_(i)R_(j) wherein R_(h) and R_(i) are independently H, F,C₁₋₄ alkyl, C₁₋₃ alkoxy, or taken together with the carbon atom to whichthey are attached, form C₃₋₈ cycloalkyl or 4- to 7-membered heterocyclylring; and R_(j) is H, C₁₋₆ alkyl, C₁₋₅ fluoroalkyl, (C₁₋₃ alkoxy)-(C₁₋₃alkylene), C₃₋₈ cycloalkyl, C₃₋₈ heterocyclyl, aryl, or heteroaryl; andp is 1, 2, or 3. Included in this embodiment are compounds of Formulas(I), (II), (III), or (IV).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, R_(a), R_(b), R_(d), and n are defined in the firstaspect with the proviso that at least one R_(3a) is—O(CH₂)₁₋₄NR_(a)S(O)₂(C₁₋₃ alkyl) or —O(CH₂)₁₋₄NR_(a)S(O)₂R_(w), whereinR_(w) is aryl or heteroaryl, each substituted with zero to 2substituents independently selected from F, Cl, cyano, C₁₋₃ alkyl, C₁₋₃alkoxy, —OCF₃, —OCHF₂, and C₁₋₃ fluoroalkyl; and p is 1, 2, or 3.Included in this embodiment are compounds of Formulas (I), (II), (III),or (IV).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, R_(a), R_(b), R_(d), and n are defined in the firstaspect with the proviso that at least one R_(3a) is—O(CH₂)₁₋₄OC(O)NR_(a)R_(x), —OCH(R_(d))(CH₂)₁₋₃OC(O)NR_(a)R_(x),—OCR_(d)R_(d)(CH₂)₁₋₃OC(O)NR_(a)R_(x), —O(CH₂)₁₋₃CH(R_(d))OC(O)NR_(a)R_(x), —O(CH₂)₁₋₃CR_(d)R_(d)OC(O)NR_(a)R_(x),—OCH(R_(d))CH(R_(d))(CH₂)₀₋₂OC(O)NR_(a)R_(x), or—OCR_(d)R_(d)CR_(d)R_(d)(CH₂)₀₋₂OC(O)NR_(a)R_(x), wherein R_(x) isselected from H, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, aryl, heteroaryl, and—CH₂(heteroaryl), each aryl and heteroaryl substituted with zero to 2substituents independently selected from F, Cl, Br, —CN, —OH, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ hydroxy-deuteroalkyl,C₁₋₆ hydroxyalkoxy, C₁₋₆ hydroxy-fluoroalkoxy, C₁₋₃ alkoxy, —C(O)OH,—(CH₂)₀₋₃C(O)O(C₁₋₃ alkyl), —(CH₂)₁₋₃OP(O)(OH)₂, —CH₂(morpholinyl),—C(O)NH₂, —C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ alkyl)₂, —C(O)NR_(a)(C₁₋₆hydroxyalkyl), —C(O)NR_(b)R_(b), —S(O)₂NR_(a)R_(a), —NH₂, —NH(C₁₋₆alkyl), —NR_(a)(C₁₋₆ hydroxyalkyl), —N(C₁₋₆ alkyl)₂, —NR_(a)C(O)(C₁₋₆alkyl), —NR_(a)C(O)(chloro, fluorophenyl), —NR_(a)S(O)₂(C₁₋₃ alkyl),—C(O)NR_(a)(CH₂)₀₋₁(hydroxymethyloxetanyl), —C(O)NR_(a)(CH₂)₀₋₁(hydroxymethyl C₃₋₆ cycloalkyl), —C(O)NR_(a)(CH₂)₀₋₁ (hydroxy C₃₋₆cycloalkyl), —C(O)NHCH₂C(CH₃)₂OP(O)(OH)₂, —C(O)(hydroxypiperidinyl),—C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl),—C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), pyrrolidinyl,morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl; and p is1, 2, or 3. Included in this embodiment are compounds of Formulas (I),(II), (III), or (IV).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, and n are defined in the first aspect with theproviso that at least one R_(3a) is F, Cl, —CN, —OH, —CH₃, —CF₃,—CHFC(CH₃)₃, cyclopropyl, —CH₂OH, —CD₂OH, —CH₂CH₂OH, —CH(OH)CH₃,—C(CH₃)₂OH, —CH(OH)C(CH₃)₃, —CD(OH)C(CH₃)₃, —CH(OH)CF₃, —CH(OH)CH₂CF₃,—CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl),—CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl substitutedwith phenyl), —CH(OH)(cyclobutyl), —CH(OH)(methoxycyclobutyl),—CH(OH)(ethoxycarbonylcyclobutyl), —CH(OH)(trifluoromethylcyclobutyl),—CH(OH)(hydroxymethylcyclobutyl), —CH(OH)(cyclobutyl substituted withphenyl), —CH(OH)(cyclohexyl), —CH(OH)(methylcyclohexyl),—CH(OH)(phenyl), —CH(OH)(isopropylphenyl),—CH(OH)(trifluoromethylphenyl), —CH(OH)(fluoro, methoxyphenyl),—CH(OH)(pyridinyl), —CH(OH)(thiazolyl), —CH(OH)(tetrahydropyranyl),—CH(OH)(methyltetrahydropyranyl), —CH₂OCH₃, —CH₂N(CH₃)₂,—CH₂NHS(O)₂(phenyl), or —CH(OH)CH₂(phenyl); and p is 1, 2, or 3.Included in this embodiment are compounds of Formulas (I), (II), (III),or (IV).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, and n are defined in the first aspect with theproviso that at least one R_(3a) is —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —OCF₃,—OCHF₂, —OCH₂(phenyl), —OCH₂(thiazolyl), —OCH₂(oxazolidinonyl),—OCH₂(amino isoxazolyl), —OCH₂(imidazolyl substituted with phenyl),—OCH₂CH₂OH, —OCH₂CH(CH₃)OH, —OCH₂CH₂OCH₃, —OCH(CH₃)CH₂OH,—OCH₂CH(OH)CH₃, —OCH(CH₃)CH(OH)CH₃, —OCH₂C(CH₃)₂OH, —OCH₂CH₂O(phenyl),—OCH₂CH₂OCH₂(phenyl), —OCH₂CH₂NH(CH₃), —OCH₂CH(CH₃)NH(methoxypyrimidinyl), —OCH₂C(O)OH, —OCH₂C(O)OCH₃, —OCH₂C(O)OCH₂CH₃,—OCH₂C(O)OC(CH₃)₃, —OCH₂C(O)NH(phenyl), —OCH₂C(O)NHCH₂(phenyl),—OCH₂C(O)(morpholinyl), —OCH₂CH₂CH₂C(O)NH(pyridinyl), —OCH₂CH₂OC(O)OCH₃,—OCH₂CH(CH₃)OC(O)NHCH₂CH₂C(O)NH₂, —OCH₂CH(CH₂CH₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OC(CH₃)₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂(phenyl))OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(pyrimidinyl), or—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(methyl pyrimidinyl); and p is 1, 2, or3. Included in this embodiment are compounds of Formulas (I), (II),(III), or (IV).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, and n are defined in the first aspect with theproviso that at least one R_(3a) is —C(O)OH, —C(O)OCH₃, or—C(O)OC(CH₃)₃; and p is 1, 2, or 3. Included in this embodiment arecompounds of Formulas (I), (II), (III), or (IV).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, and n are defined in the first aspect with theproviso that at least one R_(3a) is —NHC(O)OCH₃, —NHC(O)OC(CH₃)₃,—NHC(O)OCH₂(phenyl), —NHC(O)OCH₂(tetrahydrofuranyl), or—NHC(O)O(tetrahydropyranyl); and p is 1, 2, or 3. Included in thisembodiment are compounds of Formulas (I), (II), (III), or (IV).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, and n are defined in the first aspect with theproviso that at least one R_(3a) is —OCH₂CH₂NHC(O)OCH₃,—OCH₂CH₂NHC(O)O(tetrahydropyranyl), —OCH₂CH₂NHC(O)OCH₂(phenyl),—OCH₂CH₂NHC(O)O(methoxyphenyl), —OCH₂CH₂NHC(O)O(tetrahydrofuranyl),—OCH₂CH₂NHC(O)OCH₂(tetrahydrofuranyl), —OCH₂CH₂NHC(O)NH(pyridinyl),—OCH₂CH₂N(CH₃)C(O)NH(methylpyrimidinyl), or—OCH₂CH(CH₃)OC(O)OCH₂(aminopyridinyl); and p is 1, 2, or 3. Included inthis embodiment are compounds of Formulas (I), (II), (III), or (IV).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, and n are defined in the first aspect with theproviso that at least one R_(3a) is —OCH₂CH₂NHS(O)₂CH₃ or—OCH₂CH₂NHS(O)₂R_(w) wherein R_(w) is phenyl or pyridinyl, eachsubstituted with zero to 2 substituents independently selected from F,Cl, and —CH₃; and p is 1, 2, or 3. Included in this embodiment arecompounds of Formulas (I), (II), (III), or (IV).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₁,R₂, R₃, R_(3a), R₄, and n are defined in the first aspect with theproviso that at least one R_(3a) is —OCH₂CH₂OC(O)NHR_(z),—OCH(CH₃)CH₂OC(O)NHR_(z), —OCH₂CH(CH₃)OC(O)NHR_(z),—OCH(CH₃)CH(CH₃)(CH₂)₀₋₂OC(O)NHR_(z),—OCH₂CH(CH₂O(isobutyl))(CH₂)₀₋₂OC(O)NHR_(z),—OCH₂CH(CH₂CH₃)OC(O)NHR_(z), —OCH₂CH(CH₂OCH₃)OC(O)NHR_(z), or—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NHR_(z) wherein R_(z) is H, —CH₂CF₃,phenyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, indolyl,pyrrolo[2,3-b]pyridinyl, benzo[d]oxazolonyl, —CH₂(pyrazolyl),—CH₂(imidazolyl), or —CH₂(pyridinyl), each substituted with zero to 2substituents independently selected from F, Cl, Br, —CN, —OH, —CH₃,—CH₂CH₂CH₃, —CF₃, —CH₂OH, —CD₂OH, —CH(CH₃)OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—C(CH₃)₂OH, —CH₂CH(CH₃)OH, —CH₂C(CH₃)₂OH, —CH₂CH₂C(O)OCH₃,—CH₂OP(O)(OH)₂, —CH₂CH₂OP(O)(OH)₂, —CH₂(morpholinyl), —OCH₃, —OCH₂CH₂OH,—OCH₂CH(CH₃)OH, —OCH₂C(CH₃)₂OH, —OCH₂CH₂C(CH₃)₂OH, —OCH(CH₃)CH₂OH,—OCH₂CH(OH)CH₂OH, —OCH₂CF₂OH, —OCH₂CF₂CH₂OH, —C(O)OH, —C(O)OCH₃,—C(O)NH₂, —C(O)NH(CH₃), —C(O)N(CH₃)₂, —C(O)NH(CH₂CH₂OH),—C(O)NH(CH₂CH(CH₃)OH), —C(O)NH(CH₂C(CH₃)₂OH), —C(O)NH(CH₂C(CH₃)₂CH₂OH),—C(O)NH(CH₂CH₂C(CH₃)₂OH), —C(O)N(CH₃)CH₂CH₂OH, —C(O)N(CH₃)CH₂C(CH₃)₂OH,—C(O)NHCH₂(hydroxymethyloxetanyl), —C(O)NH(hydroxymethylcyclobutyl),—C(O)NHCH₂(hydroxycyclobutyl), —C(O)NHCH₂(hydroxymethylcyclobutyl),—C(O)NHCH₂C(CH₃)₂OP(O)(OH)₂, —C(O)(hydroxypiperidinyl),—C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl),—C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), —NH₂, —N(CH₃)₂,—NHC(O)CH₃, —NHC(O)(chloro, fluorophenyl), —NH(CH₂C(CH₃)₂OH),—N(CH₃)S(O)₂CH₃, pyrrolidinyl, morpholinyl, thiophenyl, methyltriazolyl, and oxazolidinonyl; and p is 1, 2, or 3. Included in thisembodiment are compounds of Formulas (I), (II), (III), or (IV).

One embodiment provides at least one compound of Formulas (I), (II),(III), (IV), (V), (VI), (VII), or (VIII) or a salt thereof, wherein R₃is substituted with zero to 1 R_(3a). Included in this embodiment arecompounds in which R₃ is unsubstituted.

One embodiment provides at least one compound of Formula (I) or a saltthereof, wherein R₁ is —OCH₃, —OCHF₂, —OCH₂CH₃, or —CH₂OCH₃; R₂, at eachoccurrence, is independently H, F, Cl, —CN, —CH₃, —OCH₃, or —CH₂OH; and

R₃ is:

and R₄, R_(3a), and p are defined in the first aspect.

One embodiment provides at least one compound of Formula (II) or a saltthereof, wherein R₁ is —OH, —OCH₃, —OCH₂CH₃, —OCHF₂, —OCH₂CHF₂,—CH₂OCH₃, or —NH(CH₃); R₂, at each occurrence, is independently F, Cl,—CN, —CH₃, —CH₂OH, —CH₂F, —CHF₂, or —OCH₃;

R₃ is:

and R_(3a), at each occurrence, is independently F, Cl, —CH₃, —OCH₃,—CH(OH)(trifluoromethylcyclobutyl), —OCH₂CH(CH₃)OC(O)NHR_(z), or—OCH(CH₃)CH(CH₃)OC(O)NHR_(z), wherein R_(z) is pyridinyl, pyrimidinyl,or benzo[d]oxazolonyl, each substituted with zero to 2 substituentsindependently selected from F, —OH, —CN, —CH₃, —CF₃, —CH₂OH, —CH₂CH₂OH,—OCH₂CH₂OH, —OCH₃, —CH₂CH(CH₃)OH, and —OCH₂CH₂C(CH₃)₂OH; and R₄ and pare defined in the first aspect.

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is indolyl. Included in this embodiment isa compound of Formula (I) selected from2-(difluoromethoxy)-5-(1H-indol-2-yl)-7-methylquinoxaline (5).

One embodiment provides compounds selected from one of the examples,more preferably, Examples 1 to 837, or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is benzofuranyl. Included in thisembodiment is a compound of Formulas (I), (II), (III), or (IV) selectedfrom:

-   5-(benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline (1);-   2-(difluoromethoxy)-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline    (2);-   2-(difluoromethoxy)-5-(4,5-dimethoxybenzofuran-2-yl)-7-methylquinoxaline    (6);-   5-(7-chlorobenzofuran-2-yl)-2-methoxy-7-methylquinoxaline (37);-   2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl    (2-methylpyridin-4-yl)carbamate (38);-   N-(2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl)benzenesulfonamide    (39);-   2-(difluoromethoxy)-5-(7-methoxybenzofuran-2-yl)-7-methylquinoxaline    (41);-   2-(difluoromethoxy)-5-(4-methoxybenzofuran-2-yl)-7-methylquinoxaline    (42);-   5-(4-(benzyloxy)benzofuran-2-yl)-2-methoxy-7-methylquinoxaline (43);-   5-(5-(benzyloxy)    benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline (44);    methyl    2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethylcarbamate    (46);-   tert-butyl    2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)    acetate (49);-   2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)-N-methylethanamine    (54);-   2-methoxy-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline (56);-   5-(6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxaline    (120);-   5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline    (121);-   5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxaline    (122);-   2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl    (2-methylpyridin-4-yl)carbamate (123);-   (8-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)methanol    (124);    (8-(6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)methanol    (125);-   2-((6-fluoro-2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl    (2-methylpyridin-4-yl)carbamate (126);-   5-(benzofuran-2-yl)-7-methyl-2-vinylquinoxaline (131);-   5-(benzofuran-2-yl)-2-ethyl-7-methylquinoxaline (132);-   5-(benzofuran-2-yl)-2-(difluoromethoxy)-8-methylquinoxaline (133);-   5-(benzofuran-2-yl)-2-(furan-3-yl)-7-methylquinoxaline (135);-   5-(benzofuran-2-yl)-2-methoxy-7-methylquinoxaline (175); methyl    5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate (176);-   5-(benzofuran-2-yl)-2-(1-methoxyethyl)-7-methylquinoxaline (184);-   5-(benzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline (195); and-   5-(benzofuran-2-yl)-2-ethoxy-7-methylquinoxaline (661).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is benzo[b]thiophenyl. Included in thisembodiment is a compound of Formula (I) selected from

-   5-(benzo[b]thiophen-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline    (40).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is benzo[d]imidazolyl. Included in thisembodiment is a compound of Formula (I) selected from:

-   5-(1H-benzo[d]imidazol-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline    (47); and-   2-(difluoromethoxy)-5-(5-methoxy-1H-benzo[d]imidazol-2-yl)-7-methylquinoxaline    (50).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is benzo[d]oxazolyl. Included in thisembodiment is a compound of Formula (I) selected from:

-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]oxazole (3).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is benzo[d]thiazolyl. Included in thisembodiment is a compound of Formula (I) to (III) selected from:

-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole (4);-   6-(benzyloxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (7);-   4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (8);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole    (10);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxy-4-methylbenzo[d]thiazole    (12);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-difluoro-7-methoxybenzo[d]thiazole    (13);-   tert-butyl    (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)    carbamate (14);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(thiazol-4-ylmethoxy)benzo[d]thiazole    (15);-   tetrahydrofuran-3-yl    (2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate    (16);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-phenoxyethoxy)benzo[d]thiazole    (17);-   7-(2-(benzyloxy)ethoxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (18);-   (tetrahydrofuran-2-yl)methyl    (2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-yl)oxy)ethyl)carbamate (19);-   tetrahydro-2H-pyran-4-yl    (2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-yl)oxy)ethyl)carbamate (20);-   tetrahydro-2H-pyran-4-yl    (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)    benzo[d]thiazol-7-yl)carbamate (21);-   (tetrahydrofuran-2-yl) methyl    (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)    benzo[d]thiazol-7-yl)carbamate (22);-   4-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide    (26);-   N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)    benzenesulfonamide (27);-   N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide (28);-   4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)    benzenesulfonamide (29);-   N-(2-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)    ethyl)-4-fluorobenzenesulfonamide (30);-   N-(2-((2-(2-ethyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide    (31);-   methyl    5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate    (32);-   N-(2-((2-(2-cyclopropoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide    (33);-   4-fluoro-N-(2-((2-(2-(fluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide    (34);-   2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methyl-6-((2-phenyl-1H-imidazol-5-yl)methoxy)benzo[d]thiazole    (35);-   N-benzyl-2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetamide    (36);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazole    (48);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methoxybenzo[d]thiazole    (51);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole    (52);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazole    (53);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-dimethoxybenzo[d]thiazole    (55);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxybenzo[d]thiazole    (58);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluoro-6-methoxybenzo[d]thiazole    (59);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazole    (60);-   methyl    2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole-7-carboxylate    (61);-   N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)    benzenesulfonamide (63);    (2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methanol    (64);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(methoxymethyl)benzo[d]thiazole    (65);-   N-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methyl)benzenesulfonamide    (66);-   N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazol-6-yloxy)    ethyl) benzenesulfonamide (67);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole    (68); methyl    2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethylcarbamate    (69);-   methyl    2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-7-yloxy)ethylcarbamate    (70);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-(thiazol-4-ylmethoxy)benzo[d]thiazole    (71);-   N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)    benzenesulfonamide (72);-   N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)    ethyl)benzenesulfonamide (73);-   2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethanol    (74);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d]thiazole    (75);-   benzyl    2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-ylcarbamate    (76);-   2-(2-methoxy-7-methylquinoxalin-5-yl)-6-(2-methoxyethoxy)benzo[d]thiazole    (77);-   2-(2-methoxy-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d]thiazole    (78);-   N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)    benzenesulfonamide (79);-   methyl 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)    benzo[d]thiazol-7-ylcarbamate (80);-   N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)    ethyl)-4-fluorobenzenesulfonamide (81);-   2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)    benzo[d]thiazol-7-yloxy)-N-phenylacetamide (82);-   N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)    ethyl)-4-(trifluoromethyl) benzenesulfonamide (83);-   N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)    ethyl)-2,4-difluorobenzenesulfonamide (84);-   N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)    ethyl)-3,4-difluorobenzenesulfonamide (85);-   4-chloro N (2 (2 (2    (difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide    (86);-   N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)    ethyl)-4-methylbenzenesulfonamide (87);-   4-fluoro N (2 (2 (2    (methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide    (89);-   4-fluoro N (2 (2 (2    methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy)ethyl)    benzenesulfonamide (90);-   N-(2-(2-(2-cyclopropyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide    (91);-   benzyl    2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)    ethylcarbamate (92);-   4-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (93);-   5-(5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline    (94);-   N-(2-(4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide    (95);-   2-fluoro N (2 (2 (2    (methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)    benzenesulfonamide (96);-   3-fluoro N (2 (2 (2    (methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide    (97);-   N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)    ethyl) methanesulfonamide (98);-   N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)    ethyl)benzenesulfonamide (99);-   N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)    ethyl)-2-fluorobenzenesulfonamide (100);-   N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)    ethyl)-4-fluorobenzenesulfonamide (101);-   N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)    ethyl)-3-fluorobenzenesulfonamide (102);-   6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carbonitrile    (103);-   N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)    benzenesulfonamide (104);-   N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide    (105);-   N-(2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)    ethyl)benzenesulfonamide (106);-   4-fluoro N (2 (2 (2    (methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide    (107);-   4-fluoro N (2 (2 (2 (1    fluoroethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide    (108);-   N-(2-(4-cyano-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide    (109);-   2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl    phenylcarbamate (110);-   2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl    pyridin-3-ylcarbamate (111);-   2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl    6-methoxypyridin-3-ylcarbamate (112);-   2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylpyridin-4-ylcarbamate    (113);-   N-(2-(2-(2-((difluoromethoxy)methyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide    (114);-   2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl    6-methoxypyridin-3-ylcarbamate (115);-   2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl    5-cyanopyridin-3-ylcarbamate (116);-   2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl    (6-cyanopyridin-3-yl) carbamate (117);-   2-((2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (3-cyanophenyl)carbamate (118);-   2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl    (2-chloropyrimidin-5-yl)carbamate (119);-   3-methoxy-8-(6-methoxybenzo[d]thiazol-2-yl)quinoxalin-6-yl)methanol    (127);-   2-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl    6-methylpyridin-3-ylcarbamate (128);-   2-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl    2-methylpyridin-4-ylcarbamate (129);-   methyl    6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxylate    (152);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol    (154);-   (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)    methanol (155);-   1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)    ethanol (156);-   2-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)    propan-2-ol (157);-   cyclopropyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)    benzo[d]thiazol-4-yl)methanol (158);-   1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-N,N-dimethylmethanamine    (159);-   cyclopropyl(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)    methanol (160);-   (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)    (phenyl)methanol (161);-   6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxylic    acid (162);-   (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(phenyl)    methanol (163);-   1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol    (164);-   cyclohexyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol    (165);-   cyclobutyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol    (166);-   (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(pyridin-2-yl)methanol    (167);-   (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)    (pyridin-3-yl)methanol (168);-   1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-1-d₁    (169);-   1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-d₅    (170);-   2,2,2-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol    (171);-   (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(pyridin-4-yl)methanol    (172);-   3,3,3-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)propan-1-ol    (173);-   2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)    ethanol (174);-   6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole    (183);-   2-(2-(difluoro(methoxy)methyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole    (186);-   6-methoxy-4-methyl-2-(7-methyl-2-(phenoxymethyl)quinoxalin-5-yl)benzo[d]thiazole    (187);-   1-(5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)-N,N-dimethyl    methanamine (188);-   2-(2-(ethoxymethyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole    (189);-   N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)    ethyl)-4-fluorobenzenesulfonamide (199);-   N-(2-((2-(7-chloro-2-(methoxymethyl)    quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide    (200);-   2-(7-chloro-2-(methoxymethyl)quinoxalin-5-yl)-6-methoxybenzo[d]thiazole    (201);-   2-(7-chloro-2-(methoxymethyl)quinoxalin-5-yl)-6-methoxybenzo[d]thiazole    (202);-   6-methoxy-2-(2-(methoxymethyl)-7-(trifluoromethoxy)quinoxalin-5-yl)-4-methylbenzo[d]thiazole    (203);-   methyl 8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)    quinoxaline-6-carboxylate (204);-   methyl    8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxy    methyl)quinoxaline-6-carboxylate (205);-   2-(7-fluoro-2-(methoxymethyl)quinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole    (206);-   4-fluoro-N-(2-((2-(7-fluoro-2-(methoxymethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide    (207);-   6-methoxy-2-(2-(methoxymethyl)-7-(trifluoromethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazole    (208);-   4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-(trifluoromethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide    (209);-   4-chloro-2-(7-chloro-2-(methoxymethyl)    quinoxalin-5-yl)-6-methoxybenzo[d]thiazole (210);-   3-methoxy-8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)quinoxaline-6-carbonitrile    (211);-   4-chloro-6-methoxy-2-(2-(methoxymethyl)    quinoxalin-5-yl)benzo[d]thiazole (212);-   4-fluoro-N-(2-((2-(2-(methoxymethyl)    quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)    benzenesulfonamide (213);-   2-(7-chloro-2-methoxyquinoxalin-5-yl)-4,5-difluoro-6-methoxybenzo[d]thiazole    (214);-   4-chloro-2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluoro-6-methoxybenzo[d]thiazole    (215);-   4-chloro-5-fluoro-6-methoxy-2-(2-methoxy-6,7-dimethylquinoxalin-5-yl)benzo[d]thiazole    (216);-   8-(4,5-difluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carbonitrile    (217);-   (8-(4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol    (218);-   (3-methoxy-8-(6-methoxy-4,5-dimethylbenzo[d]thiazol-2-yl)quinoxalin-6-yl)methanol    (219);-   (8-(4,5-difluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol    (220);-   8-(5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carbonitrile    (221);-   (8-(5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol    (222);-   (8-(4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2-yl)-5-fluoro-3-methoxyquinoxalin-6-yl)methanol    (224);-   8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-carboxamide    (225);-   8-(6-(2-(4-fluorophenylsulfonamido)    ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)-N,N-dimethylquinoxaline-6-carboxamide    (226);-   4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-(piperidine-1-carbonyl)    quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide    (227);-   8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-N-(2-methoxyethyl)-3-(methoxymethyl)quinoxaline-6-carboxamide    (228);-   4-fluoro-N-(2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)    ethyl) benzenesulfonamide (229);-   N-(2-((2-(7-ethynyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide    (230);-   N-(2-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide    (231);-   N-(2-((2-(7-cyano-2-(methoxymethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)    oxy)ethyl)-4-fluorobenzenesulfonamide (232);-   8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-carbonitrile    (233);-   4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)    benzenesulfonamide (234);-   4-fluoro-N-(2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)    benzenesulfonamide (235);-   N-(2-((2-(7-(1,2-dihydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide    (236);-   4-fluoro-N-(2-((2-(7-(2-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide    (237);-   N-(2-((2-(7-(aminomethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)    ethyl)-4-fluorobenzenesulfonamide (238);-   4-fluoro-N-(2-((2-(7-(1-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)    benzenesulfonamide (239);-   4-fluoro-N-(2-((2-(7-(hydroxy    (phenyl)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide    (240);-   4-fluoro-N-(2-((2-(2-methoxy-7-(prop-1-en-2-yl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)    benzenesulfonamide (241);-   4-fluoro-N-(2-((2-(7-(2-hydroxypropan-2-yl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide    (242);-   (8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)    methanol (243);    1-(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)    ethanol (244);-   (8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)    (phenyl)methanol (245);-   cyclopropyl(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol    (246);-   4-fluoro-N-(2-((2-(7-fluoro-2-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide    (247);-   (8-(5-fluoro-6-isopropoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol    (248);-   N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)    ethyl)pyridine-3-sulfonamide (249);-   ethyl    2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)    acetate (250);-   2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetic    acid (251);-   2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)    ethyl (6-methoxypyridin-3-yl)carbamate (252);-   6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (253);-   4-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)    benzo[d]thiazole (254);-   6-ethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (255);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole (256);-   4,6-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (257);-   4,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (258);-   4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (259);-   4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (260);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole    (261);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methyl-6-(trifluoromethoxy)benzo[d]thiazole    (262);-   6-(difluoromethoxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole    (263);-   methyl    2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole-6-carboxylate    (264);-   4-chloro-7-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (265);-   4-chloro-6-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (266);-   4,5-difluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (267);-   5-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (268);-   5,6-difluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (269);-   6-fluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (270);-   5-fluoro-4,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (271);-   6-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (272);-   4-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (273);-   6-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (274);-   4,6-dichloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (275);-   6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole    (276);-   5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (277);-   4,5-difluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole    (278);-   6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole    (279);-   5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole    (280);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol    (281);-   4-chloro-5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole    (282);-   4-chloro-5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (283);-   6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazole    (284);-   methyl    2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetate    (285);-   methyl    2-((5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetate    (286);-   methyl 2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-yl)oxy)acetate (287);-   2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol    (288);-   2-((5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol    (289);-   5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol    (290);-   4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-ol (291);-   methyl    2-((4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)acetate    (292);-   2-((4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanol    (293);-   5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole    (294);-   5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole    (295);-   methyl    2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)acetate    (296);-   2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethanol    (297);-   4-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole    (298);-   4-chloro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole    (299);-   (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)methanol    (300);-   (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)methanol    (301);-   2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl    (6-fluoropyridin-3-yl)carbamate (302);-   2-((5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl    (6-fluoropyridin-3-yl) carbamate (303);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (6-fluoropyridin-3-yl)carbamate (304);-   2-((4-chloro-5-fluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl(6-fluoropyridin-3-yl)carbamate    (305);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol    (306);-   6-(benzyloxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole    (307);-   (2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)methanol    (308);-   6-(methoxymethyl)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (309);-   6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5-ol    (310);-   5,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (311);-   (6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5-yl)    methanol (312);-   6-chloro-5-fluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)    benzo[d]thiazole (313);-   4-cyclopropyl-5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (314);-   6-ethoxy-4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole    (315);-   N-(2-((4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide    (316);-   N-(2-((4,5-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide    (317);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanol    (318);-   1-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)-2-methylpropan-2-ol    (319);-   2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethyl    methyl carbonate (320);-   2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-1-ol    (racemate) (321);-   1-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-2-ol    (racemate) (322);-   3-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)butan-2-ol    (diastereomeric) (323);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-1-morpholinoethanone    (324);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)    methanol (bis-deuterated) (325);-   1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)ethanol    (326);-   2-((4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-6-yl)oxy)ethanol    (327);-   1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol    (racemate) (328);-   5-fluoro-6-isopropoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)    benzo[d]thiazole (329);-   N-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide (330);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    pyridin-3-ylcarbamate (331);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (6-methoxypyridin-3-yl)carbamate (332);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (333);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (2,2,2-trifluoroethyl)carbamate (334);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    pyridin-4-ylcarbamate (335);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (2-methylpyridin-4-yl)carbamate (336);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (5-fluoropyridin-3-yl)carbamate (337);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)carbamate (338);-   2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-yl)oxy)ethyl pyridin-3-ylcarbamate (339);-   2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (6-fluoropyridin-3-yl)carbamate (340);-   2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (6-methoxypyridin-3-yl)carbamate (341);-   2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    pyridin-4-ylcarbamate (342);-   2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (343);-   (R)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl    pyridin-3-ylcarbamate (344);-   (S)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl    pyridin-3-ylcarbamate (345);-   (S)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-yl)oxy)propan-2-ylpyridin-3-ylcarbamate (346);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    pyridin-3-ylcarbamate (347);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-fluoropyridin-3-yl)carbamate (348);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    pyridin-4-ylcarbamate (349);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate    (350);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    propan-2-yl (6-cyanopyridin-3-yl)carbamate (351);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (3-amino-3-oxopropyl) carbamate (352);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    pyridazin-4-ylcarbamate (353);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (354);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-yl)oxy)propan-2-yl 1H-indol-5-ylcarbamate (355);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (1-methyl-1H-indol-5-yl)carbamate (356);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-methylpyrimidin-5-yl)carbamate (357);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    ethyl carbamate (358);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-yl)oxy)ethyl    1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (359);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    1H-indol-5-ylcarbamate (360);-   methyl    5-(((2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethoxy)carbonyl)amino)picolinate    (361);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (2-methylpyrimidin-5-yl)carbamate (362);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (5-methoxy-1,2,4-thiadiazol-3-yl)carbamate (363);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    1H-pyrazol-4-ylcarbamate (364);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    ethyl (1-methyl-1H-pyrazol-4-yl)carbamate (365);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (5-methyl-1,3,4-oxadiazol-2-yl) carbamate (366);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamate (367);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    ethyl (pyridin-3-ylmethyl)carbamate (368);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (pyridin-4-ylmethyl)carbamate (369);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (5-methyl-1,3,4-thiadiazol-2-yl)carbamate (370);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-cyanopyridin-3-yl)carbamate (371);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    pyridin-3-ylcarbamate (372);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (373);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(trifluoromethyl)pyridin-3-yl)carbamate (374);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    3H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (375);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (4-methylpyridin-3-yl) carbamate (376);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)    benzo[d]thiazol-6-yl)oxy)propan-2-yl(6-methylpyridin-3-yl)carbamate    (377);-   methyl    4-(((2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethoxy)carbonyl)amino)-1-methyl-1H-pyrrole-2-carboxylate    (378);-   1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-isobutoxypropan-2-yl    pyridin-3-ylcarbamate (379);-   1-(benzyloxy)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    pyridin-3-ylcarbamate (380);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl    (6-methoxypyridin-3-yl)carbamate (racemate) (381);-   (S)-2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl    (6-methoxypyridin-3-yl)carbamate (382);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (2-chlorothiazol-4-yl)carbamate (383);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    thiazol-5-ylcarbamate (384);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(hydroxymethyl)pyridin-3-yl)carbamate (385);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (386);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (387);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy) pyridin-4-yl)carbamate (388);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (389);-   (2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylamino)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (390);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-carbamoylpyridin-3-yl)carbamate (391);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-((2-hydroxyethyl) carbamoyl)pyridin-3-yl)carbamate (392);-   (2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (393);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    ((1-methyl-1H-imidazol-4-yl)methyl)carbamate (394);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (6-cyanopyridin-3-yl)carbamate (395);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (pyridin-2-ylmethyl)carbamate (396);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    ((1-methyl-1H-imidazol-4-yl)methyl)carbamate (397);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    ((1-methyl-1H-pyrazol-3-yl)methyl)carbamate (398);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    ((1-methyl-1H-pyrazol-4-yl)methyl)carbamate (399);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-cyanopyrimidin-5-yl)carbamate (400);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-chloropyrimidin-5-yl)carbamate (401);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-fluoro-5-methylpyridin-3-yl)carbamate (402);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-bromopyridin-3-yl)carbamate (403);-   (2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    pyridin-3-ylcarbamate (404);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-methylpyridin-3-yl)carbamate (405);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (406);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methoxypyrimidin-5-yl)carbamate (407);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-methoxypyrimidin-5-yl)carbamate (408);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    pyrimidin-5-ylcarbamate (409);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    pyrimidin-5-ylcarbamate (410);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    phenylcarbamate (411);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methoxypyridin-4-yl)carbamate (412);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    pyridazin-4-ylcarbamate (413);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-propylpyrimidin-5-yl)carbamate (414);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(trifluoromethyl)pyrimidin-5-yl)carbamate (415);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-methylpyridazin-3-yl)carbamate (416);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-methylpyrazin-2-yl)carbamate (417);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-methylpyridazin-4-yl)carbamate (418);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-methylpyridin-3-yl)carbamate (419);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-methoxypyridin-3-yl)carbamate (420);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-cyanopyridin-3-yl)carbamate (421);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-methoxy-5-methylpyridin-3-yl)carbamate (422);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    pyridin-3-ylcarbamate (423);-   2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (2-methylpyrimidin-5-yl)carbamate (424);-   (2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (425);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(morpholine-4-carbonyl)pyridin-3-yl)carbamate (426);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-carbamoylpyridin-4-yl)carbamate (427);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(methylcarbamoyl)pyridin-4-yl)carbamate (428);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-carbamoylpyrimidin-5-yl)carbamate (429);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(methylcarbamoyl)pyrimidin-5-yl)carbamate (430);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(dimethylcarbamoyl)pyrimidin-5-yl)carbamate (431);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(methylcarbamoyl)pyridin-3-yl)carbamate (432);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-carbamoylpyridin-3-yl)carbamate (433);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-carbamoylpyridin-3-yl)carbamate (434);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(morpholine-4-carbonyl)pyridin-3-yl)carbamate (435);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(methylcarbamoyl)pyridin-3-yl)carbamate (436);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(morpholine-4-carbonyl)pyrimidin-5-yl)carbamate (437);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(dimethylcarbamoyl)pyridin-3-yl)carbamate (438);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(((R)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (439);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(methylcarbamoyl)pyrimidin-5-yl)carbamate (440);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (441);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-((2-hydroxyethyl)carbamoyl)pyridin-4-yl)carbamate (442);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(methylcarbamoyl)pyridin-4-yl)carbamate (443);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-carbamoylpyridin-4-yl)carbamate (444);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)carbamate (445);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-((3-hydroxy-3-methylbutyl)carbamoyl)pyridin-3-yl)carbamate (446);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(dimethylcarbamoyl)pyridin-4-yl)carbamate (447);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate    (448);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(((R)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (449);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (450);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((2-hydroxyethyl)carbamoyl)pyridin-4-yl)carbamate (451);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((R)-2-hydroxypropyl)carbamoyl)pyridin-4-yl)carbamate (452);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-carbamoylpyridin-4-yl)carbamate (453);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-carbamoylpyrimidin-5-yl)carbamate (454);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((2-hydroxyethyl)carbamoyl)pyrimidin-5-yl)carbamate (455);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((2-hydroxyethyl)carbamoyl)pyrimidin-5-yl)carbamate (456);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((2-hydroxy-2-methylpropyl)carbamoyl)pyrimidin-5-yl)carbamate    (457);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((3-hydroxy-3-methylbutyl)carbamoyl)pyrimidin-5-yl)carbamate    (458);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)carbamate (459);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate    (460);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((S)-2-hydroxypropyl)carbamoyl)pyridin-4-yl)carbamate (461);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((S)-2-hydroxypropyl)carbamoyl)pyrimidin-5-yl)carbamate (462);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((1-hydroxycyclobutyl)methyl)carbamoyl)pyrimidin-5-yl)carbamate    (463);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-((3-hydroxy-3-methylbutyl)carbamoyl)pyridin-3-yl)carbamate (464);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-4-yl)carbamate    (465);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(methylcarbamoyl)pyridin-4-yl)carbamate (466);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(dimethylcarbamoyl)pyridin-4-yl)carbamate (467);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(dimethylcarbamoyl)pyrimidin-5-yl)carbamate (468);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(2-hydroxyethyl)carbamoyl)pyrimidin-5-yl)carbamate (469);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(((3-(hydroxymethyl)oxetan-3-yl)methyl)carbamoyl)pyridin-3-yl)carbamate    (470);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((2-hydroxyethyl)(methyl)carbamoyl)pyridin-3-yl)carbamate (471);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((3-hydroxy-2,2-dimethylpropyl)carbamoyl)pyridin-3-yl)carbamate    (472);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamate    (473);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((2-hydroxy-2-methylpropyl)(methyl)carbamoyl)pyridin-3-yl)carbamate    (474);-   R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((R)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate    (475);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((R)-3-(hydroxymethyl)pyrrolidine-1-carbonyl)pyridin-3-yl)carbamate    (476);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((S)-2-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate    (477);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((S)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate    (478);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((S)-3-(hydroxymethyl)pyrrolidine-1-carbonyl)pyridin-3-yl)carbamate    (479);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((R)-2-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate    (480);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-((S)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (481);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-((S)-3-(hydroxymethyl)pyrrolidine-1-carbonyl)pyridin-3-yl)carbamate    (482);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-((R)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (483);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((S)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (484);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((R)-3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (485);-   (2R,3S)-3-((2-(2,7-dimethylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-((R)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate    (486);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-((S)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate    (487);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((R)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate    (488);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-((S)-3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate    (489);-   (2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (490);-   (2R,3S)-3-((5-fluoro-2-(7-methyl-2-propoxyquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate    (491);-   (2R,3S)-3-((5-fluoro-2-(2-isopropoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    butan-2-yl (2-methylpyrimidin-5-yl)carbamate (492);-   (2R,3S)-3-((5-fluoro-2-(2-(2-hydroxyethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (493);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(hydroxymethyl)pyridin-4-yl)carbamate (494);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(hydroxymethyl)pyridin-4-yl)carbamate (495);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (496);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)carbamate (497);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (498);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(hydroxymethyl)pyridin-3-yl)carbamate (499);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (500);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)carbamate (501);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (502);-   4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole    (503);-   2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole (504);-   2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole    (505);-   4-chloro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole    (506);-   5-chloro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole    (507);-   6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole    (509);-   6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole    (510);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (512);-   (2R,3S)-3-((2-(6-chloro-3-ethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (513);-   (2R,3S)-3-((5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (514);-   (2R,3S)-3-((2-(6-chloro-3-(difluoromethoxy)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (515);-   1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-methoxypropan-2-yl    pyridin-3-ylcarbamate (rac) (516);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    pyridin-3-ylcarbamate (517);-   4-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-N-(pyridin-3-yl)butanamide    (518);-   1-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    ethyl)-3-(pyridin-3-yl)urea (519);-   1-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    ethyl)-1-methyl-3-(2-methylpyrimidin-5-yl)urea (520);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    butan-2-yl (6-(morpholinomethyl)pyridin-3-yl)carbamate (521);-   (2R,3S)-3-((2-(2-(dimethylamino)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (522);-   5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinic    acid, TFA (523);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    butan-2-yl carbamate (524);-   1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-isobutoxypropan-2-yl    (2-methylpyrimidin-5-yl)carbamate (rac) (525);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (526);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate    (527);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (528);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (529);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    propan-2-yl    (6-((2-methyl-2-(phosphonooxy)propyl)carbamoyl)pyridin-3-yl)carbamate,    TFA (530);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate, TFA    (531);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((phosphonooxy)methyl)pyrimidin-5-yl)carbamate (532);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-hydroxypyridin-3-yl)carbamate (533);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)    butan-2-yl (5-(2-hydroxyethoxy)pyridin-3-yl)carbamate (534);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-((S)-1-hydroxyethyl)pyrimidin-5-yl)carbamate    (535);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)    butan-2-yl (2-(((R)-1-hydroxyethyl)pyrimidin-5-yl)carbamate (536);-   2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (537);-   (2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (538);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (539);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (540);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (541);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (542);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (543);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (5-(hydroxymethyl)-6-methylpyridin-3-yl)carbamate (544);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(2-hydroxyethyl)pyridin-4-yl)carbamate (545);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(hydroxymethyl)pyridin-3-yl)carbamate (546);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethyl)pyridin-4-yl)carbamate (547);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((R)-1-hydroxypropan-2-yl)oxy)pyridin-4-yl)carbamate (549);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((R)-2-hydroxypropoxy)pyridin-4-yl)carbamate (550);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (552);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (553);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (554);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (555);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (556);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (557);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (558);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (559);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (560);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxy-2-methylpropyl)pyridin-4-yl)carbamate (561);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)carbamate (562);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (563);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (564);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (565);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate    (566);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (567);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (568);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate (569);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate (570);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (571);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (572);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (573);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (574);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxy-2-methylpropoxy)pyrimidin-5-yl)carbamate (575);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(2-hydroxy-2-methylpropoxy)pyrimidin-5-yl)carbamate (576);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxy-2-methylpropyl)pyrimidin-5-yl)carbamate (577);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (578);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (579);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (580);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (581);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate    (582);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(((R)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate    (583);-   (2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (584);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((S)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate (585);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (586);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((R)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate (587);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-((S)-2,3-dihydroxypropoxy)pyrimidin-5-yl)carbamate    (588);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-methylpyrimidin-5-yl)carbamate (589);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-methylpyridin-3-yl)carbamate (590);-   (R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    pyrimidin-5-ylcarbamate (591);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-methylpyridin-3-yl)carbamate (592);-   methyl    3-(5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidin-2-yl)propanoate    (593);-   (2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    pyridin-3-ylcarbamate (594);-   (2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (595);-   (R)-(5-aminopyridin-2-yl)methyl    (1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl)    carbonate (596);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-(dimethylamino)pyrimidin-5-yl)carbamate (597);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(dimethylamino)pyrimidin-5-yl)carbamate (598);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(dimethylamino)pyridin-3-yl)carbamate (599);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(2-oxooxazolidin-3-yl)pyridin-3-yl)carbamate (600);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-acetamidopyridin-3-yl)carbamate (601);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-aminopyridin-3-yl)carbamate (602);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-morpholinopyridin-3-yl)carbamate (603);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(3-chloro-4-fluorobenzamido)pyrimidin-5-yl)carbamate (604);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(pyrrolidin-1-yl)pyridin-3-yl)carbamate (605);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-((2-hydroxy-2-methylpropyl)amino)pyrimidin-5-yl)carbamate (606);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(N-methylmethylsulfonamido)pyrimidin-5-yl)carbamate (607);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-morpholinopyrimidin-5-yl)carbamate (608);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-(2-oxooxazolidin-3-yl)pyridin-3-yl)carbamate (609);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-acetamidopyridin-3-yl)carbamate (610);-   (R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl    (5-(hydroxymethyl)pyridin-3-yl)carbamate (611);-   (2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ol    (612);-   (2R,3S)-3-((2-(2-carbamoyl-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)    butan-2-yl (2-methylpyrimidin-5-yl)carbamate (613);-   (2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (614);-   (2R,3S)-3-((2-(2-(dimethylcarbamoyl)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (615);-   (2R,3S)-3-((5-fluoro-2-(2-((2-hydroxyethyl)carbamoyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (616);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-(hydroxymethyl)pyridin-3-yl)carbamate (617);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (618);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(hydroxymethyl)pyridin-4-yl)carbamate (619);-   (2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(1-hydroxyethyl)pyrimidin-5-yl)carbamate (620);-   2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    isothiazol-5-ylcarbamate (621);-   (R)-5-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)methyl)oxazolidin-2-one    (622);-   4-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)methyl)oxazol-2-amine    (623);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-(phosphonooxy)ethyl)pyrimidin-5-yl)carbamate (624);-   2-(6-chloro-3-(methoxymethyl)quinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole    (625);-   2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole    (626);-   2-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)propan-2-ol    (627);-   1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol    (628);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)    (phenyl)methanol (629);-   1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethyl    propan-1-ol (630);-   1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2-phenylethanol    (631);-   1-(5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol    (632);-   2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)    ethanol (633);-   4-(1-fluoro-2,2-dimethylpropyl)-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benz    o[d]thiazole (634);-   4-(benzyloxy)-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole    (635);-   1-(2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxy    benzo[d]thiazol-4-yl)-2,2-dimethyl propan-1-ol (636);-   1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethyl    propan-1-ol (637);-   2-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    (5-cyanopyridin-3-yl)carbamate (638);-   8-(4-(1-hydroxy-2,2-dimethylpropyl)-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carbonitrile    (639);-   1-(6-ethoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol    (640);-   2-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol    (641);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(3-(trifluoromethyl)phenyl)methanol    (642);-   (2-isopropylphenyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol    (643);-   ethyl    1-(hydroxy(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methyl)cyclobutanecarboxylate    (644);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (645);-   (1-(hydroxymethyl)cyclobutyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol    (646);-   (2R,3S)-3-((2-(6-chloro-3-ethylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate    (647);-   (2R,3S)-3-((5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate    (648);-   (2R,3S)-3-((2-(6-chloro-3-ethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (649);-   (2R,3S)-3-((2-(6-chloro-3-(difluoromethoxy)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (650);-   (2R,3S)-3-((2-(6-chloro-3-(2,2-difluoroethoxy)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (651);-   (2R,3S)-3-((2-(6-chloro-3-(methylamino)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)    butan-2-yl (2-methylpyrimidin-5-yl)carbamate (652);-   (2R,3S)-3-((2-(6-(difluoromethyl)-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (653);-   (2R,3S)-3-((5-fluoro-2-(6-(fluoromethyl)-3-methoxyquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (654);-   (2R,3S)-3-((2-(6-cyano-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (655);-   (2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanol    (656);-   (2R,3S)-3-((2-(3,6-dimethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (657);-   2-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl    pyridin-4-ylcarbamate (658);-   (2R,3S)-3-((2-(3-(difluoromethoxy)-6-methylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (659);-   (2R,3S)-3-((2-(3-ethoxy-6-methylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (660);-   5-(benzofuran-2-yl)-2-ethoxy-7-methylquinoxaline (661);-   4-methoxyphenyl    (2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate    (662);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol    (663);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol    (664);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-phenylcyclobutyl)methanol    (665);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-methoxycyclobutyl)methanol    (666);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclopropyl)methanol    (667);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-phenylcyclopropyl)methanol    (668);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanol    (669);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-methylcyclopropyl)methanol    (671);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-methylcyclohexyl)methanol    (672);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(thiazol-2-yl)methanol    (673);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(4-methyltetrahydro-2H-pyran-4-yl)methanol    (674);-   (3-fluoro-5-methoxyphenyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol    (675);-   (6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(1-methylcyclohexyl)methanol    (676);-   1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethan-1-ol    (677);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl (2-methylpyrimidin-5-yl)carbamate (678);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl (2-methoxypyrimidin-5-yl)carbamate (679);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl pyridin-4-ylcarbamate (680);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl (6-methylpyridin-3-yl)carbamate (681);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl (5-fluoropyridin-3-yl)carbamate (682);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (683);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl pyridin-3-ylcarbamate (684);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (685);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl (2-(3-hydroxypropyl)pyrimidin-5-yl)carbamate (686);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl (6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate    (687);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate    (688);-   methyl    (R)-5-((((1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate    (689);-   methyl    (R)-5-((((1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate    (690);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-(2-hydroxyethyl)pyridin-3-yl)carbamate (691);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate    (692);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-(((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate    (693);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-(hydroxymethyl)pyridin-3-yl)carbamate (694);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (695);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-(2-hydroxyethyl)pyridin-4-yl)carbamate (696);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (697);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl pyridazin-4-ylcarbamate (698);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate    (699);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (700);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (701);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate    (702);-   (2R,3S)-3-((5-fluoro-2-(6-fluoro-3-methoxyquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (772);-   (2R,3S)-3-((5-fluoro-2-(6-(hydroxymethyl)-3-methoxyquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate    (773);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-fluoropyridin-3-yl)carbamate (782);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(trifluoromethyl)pyridin-3-yl)carbamate (783);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-methoxypyridin-3-yl)carbamate (784);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-methoxypyridin-3-yl)carbamate (785);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-cyanopyridin-3-yl)carbamate (786);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (5,6-dimethylpyridin-3-yl)carbamate (787);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    pyridin-3-ylcarbamate (788);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-fluoropyridin-3-yl)carbamate (789);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    pyridin-4-ylcarbamate (790);-   (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (795);-   (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (796);-   (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-fluoropyridin-3-yl)carbamate (797);-   (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    pyridin-4-ylcarbamate (798);-   (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    pyridin-3-ylcarbamate (799);-   (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (5,6-dimethylpyridin-3-yl)carbamate (800);-   (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-methoxypyridin-3-yl)carbamate (801);-   (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-cyanopyridin-3-yl)carbamate (802);-   (2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-methoxypyridin-3-yl)carbamate (803);-   (2R,3S)-3-((4-chloro-5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl    (5-fluoropyridin-3-yl)carbamate (804);-   1-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol    (806);-   6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(methoxymethyl)benzo[d]thiazole    (808);-   1-(2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol    (817);-   (R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl    (6-cyanopyridin-3-yl)carbamate (818);-   (R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl    (2-methylpyrimidin-5-yl)carbamate (819);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methoxypyrimidin-5-yl)carbamate    (820);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-methoxypyridin-3-yl)carbamate    (821);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-methylpyridin-3-yl)carbamate    (822);-   (2R,3S)-3-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-methylpyridin-3-yl)carbamate    (823);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate    (824);-   (2R,3S)-3-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate    (825);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(5-cyanopyridin-3-yl)carbamate    (826);-   (2R,3S)-3-((2-(2-(2,2-difluoroethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (827);-   (2R,3S)-3-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-cyanopyridin-3-yl)carbamate (828);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-cyanopyridin-3-yl)carbamate (829);-   methyl    5-(((((2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate    (830);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(hydroxymethyl)pyridin-3-yl)carbamate (831);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(methylcarbamoyl)pyridin-3-yl)carbamate (832);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)    butan-2-yl (6-carbamoylpyridin-3-yl)carbamate (833);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(dimethylcarbamoyl)pyridin-3-yl)carbamate (834);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (835);-   (2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl    (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (836); and-   2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole    (837);

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is imidazol[1,2-a]pyridinyl. Included inthis embodiment is a compound of Formula (I) selected from:

-   2-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-2-yl)-7-methylquinoxaline    (45).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is thiazolo[4,5-b]pyridinyl. Included inthis embodiment is a compound of Formula (I) selected from:

-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazolo[4,5-b]pyridine    (9);-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxythiazolo[4,5-c]pyridine    (24);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine    (146); and-   2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine (809).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is thiazolo[5,4-b]pyridinyl. Included inthis embodiment is a compound of Formula (I) selected from:

-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methoxythiazolo[5,4-b]pyridine    (23);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine    (147);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine    (148);-   7-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyridine    (149);-   5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine    (150);-   7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyridine    (151);-   5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine    (179);-   6-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine    (180);-   5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine    (181);-   6-fluoro-5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine    (182);-   5-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine    (191);-   (5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-7-yl)    methanol (192);-   4-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)    benzenesulfonamide (193);-   4-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)benzenesulfonamide    (194);-   2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)eth    yl pyridin-3-ylcarbamate (196);-   2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)eth    yl (6-cyanopyridin-3-yl)carbamate (197);-   2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl    (6-cyanopyridin-3-yl)carbamate (198);-   (3-methoxy-8-(5-methoxy-7-methylthiazolo[5,4-b]pyridin-2-yl)quinoxalin-6-yl)methanol    (223);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (708);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    pyridin-3-ylcarbamate (709);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-methylpyridin-3-yl)carbamate (710);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-methoxypyrimidin-5-yl)carbamate (711);-   methyl    5-(((((2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate    (712);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    pyridin-4-ylcarbamate (713);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (5-fluoropyridin-3-yl)carbamate (714);-   methyl    5-(((((2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate    (715);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    pyrimidin-5-ylcarbamate (716);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(2-hydroxyethyl)pyridin-4-yl)carbamate (717);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate (718);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (719);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate (720);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (721);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(((R)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (722);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(hydroxymethyl)pyridin-4-yl)carbamate (723);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-((S)-1-hydroxypropan-2-yl)oxy)pyrimidin-5-yl)carbamate (724);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (725);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(2,2-difluoro-3-hydroxypropoxy)pyridin-3-yl)carbamate (726);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate (727);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (728);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate (729);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(3-hydroxy-3-methylbutoxy)pyrimidin-5-yl)carbamate (730);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (731);-   (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl pyridin-3-ylcarbamate (733);-   (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-fluoro-5-methylpyridin-3-yl)carbamate (734);-   (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(5-cyanopyridin-3-yl)carbamate (735);-   (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-chloropyrimidin-5-yl)carbamate (736);-   (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-methylpyrimidin-5-yl)carbamate (737);-   (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-methoxypyrimidin-5-yl)carbamate (738);-   (R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl pyridin-3-ylcarbamate (740);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl    (6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate    (741);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl-   (6-(((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamate    (742);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-(3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate    (743);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-((S)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate    (744);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-((R)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate    (745);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-(4-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate    (746);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-(((R)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate    (747);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate    (748);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-carbamoylpyrimidin-5-yl)carbamate (749);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate (750);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-((2-hydroxy-2-methylpropyl)carbamoyl)pyrimidin-5-yl)carbamate    (751);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(((R)-2-hydroxypropyl)carbamoyl)pyrimidin-5-yl)carbamate (752);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(((S)-2-hydroxypropyl)carbamoyl)pyrimidin-5-yl)carbamate (753);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-carbamoylpyridin-3-yl)carbamate (754);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-carbamoylpyrimidin-5-yl)carbamate (755);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(3-(hydroxymethyl)morpholine-4-carbonyl)pyridin-3-yl)carbamate    (756);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)    oxy)butan-2-yl    (6-((S)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate    (757);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(3-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (758);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(4-hydroxypiperidine-1-carbonyl)pyridin-3-yl)carbamate (759);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-((R)-3-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl)carbamate    (760);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(((1-(hydroxymethyl)cyclobutyl)methyl)carbamoyl)pyridin-3-yl)carbamate    (761);-   N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)    ethyl)-4-methylbenzenesulfonamide (762);-   6-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine    (763);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (764);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate (765);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(1-hydroxyethyl)pyridin-3-yl)carbamate (766);-   (2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (6-(1-hydroxyethyl)pyridin-3-yl)carbamate (767);-   (R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate (768);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)    butan-2-yl (2-methylpyrimidin-5-yl)carbamate (769);-   (R)-1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)pro    pan-2-yl (2-methylpyrimidin-5-yl)carbamate (770);-   (2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (771);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)    butan-2-yl (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (774);-   (2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (775);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (5-fluoropyridin-3-yl)carbamate (776);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)    butan-2-yl (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate (777);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)    butan-2-yl (2-(3-hydroxy-3-methylbutoxy)pyridin-4-yl)carbamate    (778);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)    butan-2-yl (6-(2-hydroxyethoxy)pyridin-3-yl)carbamate (779);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)    butan-2-yl (2-(2-hydroxyethoxy)pyridin-4-yl)carbamate (780);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)    butan-2-yl (6-(2-hydroxyethyl)pyridin-3-yl)carbamate (781);-   (2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-methylpyrimidin-5-yl)carbamate (791);-   (2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (792);-   (2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)    butan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (793);-   (R)-1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)pro    pan-2-yl (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (794);-   1-(5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-7-yl)-2,2-dimethylpropan-1-ol    (807);-   2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl    pyridin-3-ylcarbamate (810);-   2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)    ethyl (6-fluoro-5-methylpyridin-3-yl)carbamate (811);-   2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)    ethyl (6-(thiophen-2-yl)pyridin-3-yl)carbamate (812);-   (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl    (2-methylpyrimidin-5-yl)carbamate (813);-   (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl    (2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate (814);-   (R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)    propan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate    (815);-   (2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl    (2-(hydroxymethyl)pyrimidin-5-yl)carbamate (816); and-   1-(2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol    (817).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is 4,5,6,7-tetrahydrobenzo[d]thiazolyl.Included in this embodiment is a compound of Formula (I) selected from:

-   2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol    (138);-   7-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole    (139);-   6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole    (140);-   2-(2-methoxy-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole    (141);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol    (143);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole    (144);-   2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol    (145); and-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole    (178).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is 4,5,6,7-tetrahydrobenzofuranyl.Included in this embodiment is a compound of Formula (I) selected from:tert-butyl(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)carbamate (25).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is 6,7-tetrahydrothiazolo[5,4-c]pyridinyl.Included in this embodiment is a compound of Formula (I) selected from:tert-butyl2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(11) and methyl2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(62).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl. Included in thisembodiment is a compound of Formula (I) selected from:

-   2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazole    (137).

One embodiment provides compounds of Formulas (I), (II), (III), or (IV)or a salt thereof, wherein R₃ is 5,6-dihydro-4H-cyclopenta[d]thiazolyl.Included in this embodiment is a compound of Formula (I) selected from:

-   2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole    (136); and    2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazol-5-yl)    ethanol (142).

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of the aspects and/or embodimentsof the invention noted herein. It is understood that any and allembodiments of the present invention may be taken in conjunction withany other embodiment or embodiments to describe additional embodiments.It is also to be understood that each individual element of theembodiments is meant to be combined with any and all other elements fromany embodiment to describe an additional embodiment.

Definitions

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. Embodiments identified herein as exemplary or preferred areintended to be illustrative and not limiting.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

As used herein, the phase “compounds” refers to at least one compound.For example, a compound of Formula (I) includes a compound of Formula(I) and two or more compounds of Formula (I).

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Listed below are definitions of various terms used to describe thepresent invention. These definitions apply to the terms as they are usedthroughout the specification (unless they are otherwise limited inspecific instances) either individually or as part of a larger group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, andI.

The term “cyano” refers to the group —CN.

The term “amino” refers to the group —NH₂.

The term “alkyl” as used herein, refers to both branched andstraight-chain saturated aliphatic hydrocarbon groups containing, forexample, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1to 4 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl(e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl,3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscriptafter the symbol “C”, the subscript defines with more specificity thenumber of carbon atoms that a particular group may contain. For example,“C₁₋₄ alkyl” denotes straight and branched chain alkyl groups with oneto four carbon atoms.

The term “fluoroalkyl” as used herein is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupssubstituted with one or more fluorine atoms. For example, “C₁₋₄fluoroalkyl” is intended to include C₁, C₂, C₃, and C₄ alkyl groupssubstituted with one or more fluorine atoms. Representative examples offluoroalkyl groups include, but are not limited to, —CF₃ and —CH₂CF₃.

The term “aminoalkyl” as used herein is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupssubstituted with one or more amino groups. For example, “C₁₋₄aminoalkyl” is intended to include C₁, C₂, C₃, and C₄ alkyl groupssubstituted with one or more amino groups. Representative examples ofaminoalkyl groups include, but are not limited to, —CH₂NH₂, —CH₂CH₂NH₂,and —CH₂CH(NH₂)CH₃.

The term “hydroxyalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more hydroxyl groups. Forexample, “hydroxyalkyl” includes —CH₂OH, —CH₂CH₂OH, and C₁₋₄hydroxyalkyl.

The term “hydroxy-deuteroalkyl” includes both branched andstraight-chain saturated alkyl groups substituted with one or morehydroxyl groups and one or more deuterium atoms. Representative examplesof hydroxy-deuteroalkyl groups include, but are not limited to, —CD₂OHand —CH(CD₃)₂OH.

The term “hydroxy-fluoroalkyl” includes both branched and straight-chainsaturated alkyl groups substituted with one or more hydroxyl groups andone or more fluorine atoms. Representative examples ofhydroxy-fluoroalkyl groups include, but are not limited to, —CF₂OH and—CF₂CH₂OH.

As used herein, “alkylene” refers to a bivalent alkyl radical having thegeneral formula —(CH₂)_(n)—, where n is 1 to 10. Non-limiting examplesinclude methylene, dimethylene, trimethylene, tetramethylene,pentamethylene, and hexamethylene. For example, “C₁₋₆ alkylene” denotesstraight and branched chain alkylene groups with one to six carbonatoms. Further, for example, “C₀₋₄ alkylene” denotes a bond and straightand branched chain alkylene groups with one to four carbon atoms.

As used herein, “deuteroalkylene” refers to an alkylene group in whichone or more hydrogen atoms have been replaced with deuterium atoms. Forexample, “C₁₋₆ deuteroalkylene” denotes straight and branched chaindeuteroalkylene groups with one to six carbon atoms.

As used herein, “fluoroalkylene” refers to an alkylene group substitutedwith one or more fluorine atoms. For example, “C₁₋₆ fluoroalkylene”denotes straight and branched chain fluoroalkylene groups with one tosix carbon atoms.

The term “alkenyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least onecarbon-carbon double bond. Exemplary such groups include ethenyl orallyl. For example, “C₂₋₆ alkenyl” denotes straight and branched chainalkenyl groups with two to six carbon atoms.

The term “alkynyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least one carbon tocarbon triple bond. Exemplary such groups include ethynyl. For example,“C₂₋₆ alkynyl” denotes straight and branched chain alkynyl groups withtwo to six carbon atoms.

The term “cycloalkyl,” as used herein, refers to a group derived from anon-aromatic monocyclic or polycyclic hydrocarbon molecule by removal ofone hydrogen atom from a saturated ring carbon atom. Representativeexamples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in asubscript after the symbol “C”, the subscript defines with morespecificity the number of carbon atoms that a particular cycloalkylgroup may contain. For example, “C₃₋₆ cycloalkyl” denotes cycloalkylgroups with three to six carbon atoms.

The term “fluorocycloalkyl” refers to a cycloalkyl group in which one ormore hydrogen atoms are replaced by fluoro group(s).

The term “hydroxycycloalkyl” refers to a cycloalkyl group in which oneor more hydrogen atoms are replaced by hydroxyl group(s).

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom, for example, methoxygroup (—OCH₃). For example, “C₁₋₃ alkoxy” denotes alkoxy groups with oneto three carbon atoms.

The terms “fluoroalkoxy” and “—O(fluoroalkyl)” represent a fluoroalkylgroup as defined above attached through an oxygen linkage (—O—). Forexample, “C₁₋₄ fluoroalkoxy” is intended to include C₁, C₂, C₃, and C₄fluoroalkoxy groups.

The term “hydroxyalkoxy” represent a hydroxyalkyl group as defined aboveattached through an oxygen linkage (—O—). For example, “C₁₋₄hydroxyalkoxy” is intended to include C₁, C₂, C₃, and C₄ hydroxyalkoxygroups.

The term “hydroxy-fluoroalkoxy” represent a hydroxy-fluoroalkyl group asdefined above attached through an oxygen linkage (—O—). For example,“C₁₋₄ hydroxy-fluoroalkoxy” is intended to include C₁, C₂, C₃, and C₄hydroxy-fluoroalkoxy groups.

The term “cycloalkoxy,” as used herein, refers to a cycloalkyl groupattached to the parent molecular moiety through an oxygen atom, forexample, cyclopropoxy group (—O(cyclopropyl)).

The term “alkoxyalkoxy” as used herein, refers to an alkoxy groupattached through an alkoxy group to the patent molecular moiety. Forexample, “(C₁₋₃ alkoxy)-(C₁₋₆ alkoxy)” denotes a C₁₋₃ alkoxy groupattached through a C₁₋₆ alkoxy group to the parent molecular moiety.

The term “alkoxyalkylene” as used herein, refers to an alkoxy groupattached through an alkylene group to the patent molecular moiety. Forexample, “(C₁₋₃ alkoxy)-(C₁₋₃ alkylene)” denotes a C₁₋₃ alkoxy groupattached through a C₁₋₃ alkylene to the parent molecular moiety.

The term “fluoroalkoxyalkylene” as used herein, refers to a fluoroalkoxygroup attached through an alkylene group. For example, “(C₁₋₂fluoroalkoxy)-(C₁₋₂ alkylene)” denotes a C₁₋₂ fluoroalkoxy groupattached through a C₁₋₂ alkylene to the parent molecular moiety.

The term “alkoxy-fluoroalkylene” as used herein, refers to an alkoxygroup attached through a fluoroalkylene group to the patent molecularmoiety. For example, “(C₁₋₃ alkoxy)-(C₁₋₃ fluoroalkylene)” denotes aC₁₋₃ alkoxy group attached through a C₁₋₃ fluoroalkylene to the parentmolecular moiety.

The term “deuteroalkoxy-deuteroalkylene” as used herein, refers to adeuteroalkoxy group attached through a deuteroalkylene group to thepatent molecular moiety. For example, “(C₁₋₃ deuteroalkoxy)-(C₁₋₃deuteroalkylene)” denotes a C₁₋₃ deuteroalkoxy group attached through aC₁₋₃ deuteroalkylene to the parent molecular moiety.

The term “alkylthio,” as used herein, refers to an alkyl group attachedto the parent molecular moiety through a sulfur atom, for example,methylthio group (—SCH₃). For example, “C₁₋₃ alkylthio” denotesalkylthio groups with one to three carbon atoms.

The term “fluoroalkylthio,” as used herein, refers to a fluoroalkylgroup attached to the parent molecular moiety through a sulfur atom, forexample, trifluoromethylthio group (—SCF₃). For example, “C₁₋₃fluoroalkylthio” denotes fluoroalkylthio groups with one to three carbonatoms.

The term “aryl,” as used herein, refers to a group of atoms derived froma molecule containing aromatic ring(s) by removing one hydrogen that isbonded to the aromatic ring(s). Representative examples of aryl groupsinclude, but are not limited to, phenyl, naphthyl, indanyl, indenyl, and1,2,3,4-tetrahydronaphth-5-yl. The aryl ring may be unsubstituted or maycontain one or more substituents as valence allows.

The term “benzyl,” as used herein, refers to a methyl group in which oneof the hydrogen atoms is replaced by a phenyl group. The phenyl ring maybe unsubstituted or may contain one or more substituents as valenceallows.

The term “aryloxy,” as used herein, refers to an aryl group attachedthrough an oxygen group.

The term “phenoxy,” as used herein, refers to a phenyl group attachedthrough an oxygen group (—O-phenyl). The phenyl ring may beunsubstituted or may contain one or more substituents as valence allows.

The term “heteroatom” refers to oxygen (O), sulfur (S), and nitrogen(N).

The term “heterocyclo” or “heterocyclyl” may be used interchangeably andrefer to non-aromatic 3- to 7-membered monocyclic groups and 6- to11-membered bicyclic groups, in which at least one of the rings has atleast one heteroatom (0, S or N), said heteroatom containing ringpreferably having 1 to 3 heteroatoms independently selected from 0, S,and/or N. Each ring of such a group containing a heteroatom can containone or two oxygen or sulfur atoms and/or from one to four nitrogen atomsprovided that the total number of heteroatoms in each ring is four orless, and further provided that the ring contains at least one carbonatom. The nitrogen and sulfur atoms may optionally be oxidized and thenitrogen atoms may optionally be quaternized. The fused rings completingthe bicyclic group may contain only carbon atoms and may be saturated,partially saturated, or unsaturated. The heterocyclo group may beattached at any available nitrogen or carbon atom. The heterocyclo ringmay be unsubstituted or may contain one or more substituents as valenceallows.

Exemplary monocyclic heterocyclyl groups include oxetanyl, azetidinyl,pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane, and tetrahydro-1,1-dioxothienyl. Exemplary bicyclicheterocyclo groups include quinuclidinyl.

The term “heteroaryl” refers to substituted and unsubstituted aromatic5- or 6-membered monocyclic groups and 9- or 10-membered bicyclic groupswhich have at least one heteroatom (O, S or N) in at least one of therings, said heteroatom-containing ring preferably having 1, 2, or 3heteroatoms independently selected from O, S, and/or N. Each ring of theheteroaryl group containing a heteroatom can contain one or two oxygenor sulfur atoms and/or from one to four nitrogen atoms provided that thetotal number of heteroatoms in each ring is four or less and each ringhas at least one carbon atom. The fused rings completing the bicyclicgroup may contain only carbon atoms and may be saturated, partiallysaturated, or unsaturated. The nitrogen and sulfur atoms may optionallybe oxidized and the nitrogen atoms may optionally be quaternized.Heteroaryl groups which are bicyclic or tricyclic must include at leastone fully aromatic ring but the other fused ring or rings may bearomatic or non-aromatic. The heteroaryl group may be attached at anyavailable nitrogen or carbon atom of any ring. The heteroaryl ringsystem may be unsubstituted or may contain one or more substituents.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydroisoindolyl, and tetrahydroquinolinyl.

The term “heteroaryloxy,” as used herein, refers to a heteroaryl groupattached through an oxygen group to the patent molecular moiety.

The term “arylalkylene” refers to an aryl group attached through analkylene group to the patent molecular moiety. For example, “aryl(C₁₋₂alkylene)” refers to an aryl group attached through a C₁₋₂ alkylene tothe parent molecular moiety.

The term “heteroarylalkylene” refers to a heteroaryl group attachedthrough an alkylene group to the patent molecular moiety. For example,“heteroaryl(C₁₋₂ alkylene)” refers to a heteroaryl group attachedthrough a C₁₋₂ alkylene to the parent molecular moiety.

The term “aryloxyalkylene” refers to an aryloxy group attached throughan alkylene group to the patent molecular moiety. For example,“aryloxy-(C₁₋₂ alkylene)” refers to an aryloxy group attached through aC₁₋₂ alkylene to the parent molecular moiety.

The term “heteroaryloxyalkylene” refers to a heteroaryloxy groupattached through an alkylene group to the patent molecular moiety. Forexample, “heteroaryloxy-(C₁₋₂ alkylene)” refers to a heteroaryloxy groupattached through a C₁₋₂ alkylene to the parent molecular moiety.

The compounds of the present invention can be provided as amorphoussolids or crystalline solids. Lyophilization can be employed to providethe compounds as amorphous solids.

It should further be understood that solvates (e.g., hydrates) of theCompounds of the invention are also within the scope of the presentinvention. The term “solvate” means a physical association of a compoundof Formulas (I) to (VIII) with one or more solvent molecules, whetherorganic or inorganic. This physical association includes hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, ethanolates, methanolates, isopropanolates, acetonitrilesolvates, and ethyl acetate solvates. Methods of solvation are known inthe art.

In addition, compounds of Formulas (I) to (VIII), subsequent to theirpreparation, can be isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% of acompound of Formulas (I) to (VIII) (“substantially pure”), which is thenused or formulated as described herein. Such “substantially pure”compounds of Formulas (I) to (VIII) are also contemplated herein as partof the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

The compounds of the present invention are intended to include allisotopes of atoms occurring in the present compounds. Isotopes includethose atoms having the same atomic number but different mass numbers. Byway of general example and without limitation, isotopes of hydrogeninclude deuterium (D) and tritium (T). Isotopes of carbon include ¹³Cand ¹⁴C. Isotopically-labeled compounds of the invention can generallybe prepared by conventional techniques known to those skilled in the artor by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed. For example, methyl (—CH₃) also includesdeuterated methyl groups such as —CD₃.

BIOLOGY

The term “PAR4 antagonist” denotes an inhibitor of platelet aggregationwhich binds PAR4 and inhibits PAR4 cleavage and/or signaling. Typically,PAR4 activity is reduced in a dose dependent manner by at least 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to suchactivity in a control cell. The control cell is a cell that has not beentreated with the compound. PAR4 activity is determined by any standardmethod in the art, including those described herein (for example calciummobilization in PAR4 expressing cells, platelet aggregation, plateletactivation assays measuring e.g., calcium mobilization, P-selectin orCD40L release, or thrombosis and hemostasis models). In certainembodiments, platelet activation is measured by changes in the plateletcytoplasm, by changes of the platelet membrane, by changes in the levelsof analytes released by platelets, by the changes in the morphology ofthe platelet, by the ability of platelets to form thrombi or plateletaggregates in flowing or stirred whole blood, by the ability ofplatelets to adhere to a static surface which is derivatized withrelevant ligands (e.g., von Willebrand Factor, collagen, fibrinogen,other extracellular matrix proteins, synthetic fragments of any of theproteins, or any combination thereof), by changes in the shape of theplatelets, or any combinations thereof. In one embodiment, plateletactivation is measured by changes in the levels of one or more analytesreleased by platelets. For example, the one or more analytes released byplatelets can be P-selectin (CD62p), CD63, ATP, or any combinationthereof. In a particular embodiment, platelet activation is measured bythe level of binding of fibrinogen or GPIIbIIIa antibodies to platelets.In other embodiments, platelet activation is measured by the degree ofphosphorylation of vasodilator-stimulated phosphoprotein (VASP) uponplatelet activation. In yet other embodiments, platelet activation ismeasured by the level of platelet-leukocyte aggregates. In certainembodiments, platelet activation is measured by proteomics profiling.The term “PAR4 antagonist” also includes a compound that inhibits bothPAR1 and PAR4.

Preferably, compounds of the invention have IC₅₀s in the PAR4 FLIPRAssay (described hereinafter) of about 10 μM, preferably 1 μM or less,more preferably 100 nM or less, and even more preferably 10 nM or less.PAR4 FLIPR assay data for compounds of the present invention ispresented in the Table.

In some embodiments, the present invention provides a pharmaceuticalcomposition, which includes a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of Formula I-VIII,preferably, a compound selected from one of the examples, morepreferably, Examples 1 to 837, or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof, alone or incombination with another therapeutic agent.

In some embodiments, the present invention provides a pharmaceuticalcomposition which further includes another therapeutic agent(s). In apreferred embodiment, the present invention provides a pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof. Preferably, theanti-platelet agent(s) are P2Y12 antagonists and/or aspirin. Preferably,the P2Y12 antagonists are clopidogrel, ticagrelor, or prasugrel. Inanother preferred embodiment, the present invention provides apharmaceutical composition, wherein the additional therapeutic agent(s)are an anticoagulant or a combination thereof. Preferably, theanticoagulant agent(s) are a FXa inhibitor, a thrombin inhibitor, or aFXIa inhibitor. Preferably, the FXa inhibitors are apixaban,rivaroxaban, edoxaban, or betrixaban. Preferably, the thrombin inhibitoris dabigatran.

It is desirable to find compounds with advantageous and improvedcharacteristics compared with known anti-platelet agents, in one or moreof the following categories that are given as examples, and are notintended to be limiting: (a) pharmacokinetic properties, including oralbioavailability, half life, and clearance; (b) pharmaceuticalproperties; (c) dosage requirements; (d) factors that decrease bloodconcentration peak-to-trough characteristics; (e) factors that increasethe concentration of active drug at the receptor; (f) factors thatdecrease the liability for clinical drug-drug interactions; (g) factorsthat decrease the potential for adverse side-effects, includingselectivity versus other biological targets; (h) improved therapeuticindex with less propensity for bleeding; and (h) factors that improvemanufacturing costs or feasibility.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or nonhumanorganism that could potentially benefit from treatment with a PAR4antagonist. Exemplary subjects include human beings of any age with riskfactors for cardiovascular disease, or patients that have alreadyexperienced one episode of cardiovascular disease. Common risk factorsinclude, but are not limited to, age, male sex, hypertension, smoking orsmoking history, elevation of triglycerides, elevation of totalcholesterol or LDL cholesterol.

In some embodiments, the subject is a species having a dual PAR1/PAR4platelet receptor repertoire. As used herein, the term “dual PAR1/PAR4platelet receptor repertoire” means that a subject expresses PAR1 andPAR4 in platelets or their precursors. Exemplary subjects having a dualPAR1/PAR4 platelet receptor repertoire include human beings, non-humanprimates, and guinea pigs.

In other embodiments, the subject is a species having a dual PAR3/PAR4platelet receptor repertoire. As used herein, the term “dual PAR3/PAR4platelet receptor repertoire” means that a subject expresses PAR3 andPAR4 in platelets or their precursors. Exemplary subjects having a dualPAR3/PAR4 platelet receptor repertoire include rodents and rabbits.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e; arresting its development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit and/or antagonize PAR4 and/or toprevent or treat the disorders listed herein. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi) within a blood vessel that may causeischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In another embodiment, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the secondary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, atrial fibrillation and venousthrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid interna, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, atrial fibrillation is frequently associated withthromboembolic disorders. Risk factors for atrial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population. (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N Engl. JMed., 334(11):677-681 (1996); Blom, J. W. et al., JAMA, 293(6):715-722(2005).) Hence, the most common cancers associated with thrombosis inmen are prostate, colorectal, brain, and lung cancer, and in women arebreast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular weight heparin preparations have been approvedby the FDA for these indications.

The term “pharmaceutical composition,” as used herein, means anycomposition, which contains at least one therapeutically or biologicallyactive agent and is suitable for administration to the patient. Any ofthese formulations can be prepared by well-known and accepted methods ofthe art. See, for example, Gennaro, A. R., ed., Remington: The Scienceand Practice of Pharmacy, 20th Edition, Mack Publishing Co., Easton, Pa.(2000).

The invention includes administering to a subject a pharmaceuticalcomposition that includes a compound that binds to PAR4 and inhibitsPAR4 cleavage and/or signaling (referred to herein as a “PAR4antagonist” or “therapeutic compound”).

The pharmaceutical composition is administered using methods known inthe art. Preferably, the compound is administered orally, rectally,nasally, by inhalation, topically or parenterally, e.g., subcutaneously,intraperitoneally, intramuscularly, and intravenously. The compound isoptionally formulated as a component of a cocktail of therapeutic drugsto treat a thromboembolic disorder. In one embodiment, thepharmaceutical composition is administered orally.

The therapeutic compounds described herein are formulated intopharmaceutical compositions utilizing conventional methods. For example,a PAR4 antagonist is formulated in a capsule or a tablet for oraladministration. Capsules may contain any standard pharmaceuticallyacceptable materials such as gelatin or cellulose. Tablets may beformulated in accordance with conventional procedures by compressingmixtures of a therapeutic compound with a solid carrier and a lubricant.Examples of solid carriers include starch and sugar bentonite. Thecompound is administered in the form of a hard shell tablet or a capsulecontaining a binder, e.g., lactose or mannitol, a conventional filler,and a tableting agent. Other formulations include an ointment,suppository, paste, spray, patch, cream, gel, resorbable sponge, orfoam. Such formulations are produced using methods well known in theart. The compositions of the invention are also useful for parenteraladministration, such as intravenous, subcutaneous, intramuscular, andintraperitoneal. Examples of formulations suitable for parenteraladministration include aqueous solutions of the active agent in anisotonic saline solution, a 5% glucose solution, or another standardpharmaceutically acceptable excipient. Standard solubilizing agents suchas PVP or cyclodextrins are also utilized as pharmaceutical excipientsfor delivery of the therapeutic compounds.

The preferred dose of the PAR4 antagonist is a biologically active dose.A biologically active dose is a dose that will inhibit cleavage and/orsignaling of PAR4 and have an anti-thrombotic effect. Desirably, thePAR4 antagonist has the ability to reduce the activity of PAR4 by atleast 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or morethan 100% below untreated control levels. The levels of PAR4 inplatelets is measured by any method known in the art, including, forexample, receptor binding assay, platelet aggregation, plateletactivation assays (e.g., p-selectin expression by FACS), Western blot orELISA analysis using PAR4 cleavage sensitive antibodies. Alternatively,the biological activity of PAR4 is measured by assessing cellularsignaling elicited by PAR4 (e.g., calcium mobilization or other secondmessenger assays).

In some embodiments, a therapeutically effective amount of a PAR4compound is preferably from about less than 100 mg/kg, 50 mg/kg, 10mg/kg, 5 mg/kg, 1 mg/kg, or less than 1 mg/kg. In a more preferredembodiment, the therapeutically effective amount of the PAR4 compound isless than 5 mg/kg. In a most preferred embodiment, the therapeuticallyeffective amount of the PAR4 compound is less than 1 mg/kg. Effectivedoses vary, as recognized by those skilled in the art, depending onroute of administration and excipient usage.

The activity of the PAR4 antagonists of the present invention can bemeasured in a variety of in vitro assays. Exemplary assays are shownbelow.

The Fluorometric Imaging Plate Reader (FLIPR) assay is an exemplary invitro assay for measuring the activity of the PAR4 antagonists of thepresent invention. In this assay, intracellular calcium mobilization isinduced in PAR4 expressing cells by a PAR4 agonist and calciummobilization is monitored.

AYPGKF is a known PAR4 agonist. An alternative PAR4 agonist isH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂. As shown in ExampleB of WO2013/163279, H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂was validated as a PAR4 agonist in the FLIPR assay. A side-by-sidecomparison of the IC₅₀ values of ˜180 compounds were performed usingAYPGKF versus H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂. Theresults demonstrated a strong correlation between the two assays.Additionally, H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ hasimproved agonist activity as compared to AYPGKF with an EC₅₀ that is 10fold lower than the EC₅₀ for AYPGKF in the FLIPR assay.H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ can be synthesizedusing methods well known to those of skill in the art.

The FLIPR assay can also be used as a counterscreen to test agonistactivity or PAR1 antagonist activity in a cell line that expresses bothPAR1 and PAR4. The PAR1 antagonist activity can be tested by the abilityof the compound to inhibit calcium mobilization induced by the PAR1agonist peptide SFLLRN or other PAR1 agonist peptides.

The compounds of the current invention can be tested in vitro for theirability to inhibit platelet aggregation induced by gamma-thrombin asshown below. Gamma-thrombin, a proteolytic product of alpha-thrombinwhich no longer interacts with PAR1, selectively cleaves and activatesPAR4 (Soslau, G. et al., “Unique pathway of thrombin-induced plateletaggregation mediated by glycoprotein Ib”, J. Biol. Chem.,276:21173-21183 (2001)). Platelet aggregation can be monitored in a96-well microplate aggregation assay format or using standard plateletaggregometer. The aggregation assay can also be employed to test theselectivity of the compound for inhibiting platelet aggregation inducedby PAR4 agonist peptides, PAR1 agonist peptide, ADP, or thromboxaneanalogue U46619.

The compounds of the current invention can be tested in vitro for theirability to inhibit platelet aggregation induced by alpha-thrombin asshown below. Alpha-thrombin activates both PAR1 and PAR4. The ability ofa selective PAR4 antagonist of the present invention to inhibit plateletaggregation can be measured using a standard optical aggregometer.

The compounds of the current invention can be tested in vitro for theirability to inhibit platelet aggregation induced by tissue factor asshown below. The conditions in this assay mimic the physiological eventsduring thrombus formation. In this assay, platelet aggregation in humanplatelet rich plasma (PRP) is initiated by the addition of tissue factorand CaCl₂. Tissue factor, the initiator of the extrinsic coagulationcascade, is highly elevated in human atherosclerotic plaque. Exposure ofblood to tissue factor at the atherosclerotic site triggers a robustgeneration of thrombin and induces the formation of obstructive thrombi.

The activity of the PAR4 antagonists of the present invention can alsobe measured in a variety of in vivo assays. Exemplary mammals that canprovide models of thrombosis and hemostasis to test the effectiveness ofthe PAR4 antagonists of the present invention as antithrombotic agentsinclude, but are not limited to, guinea pigs and primates. Relevantefficacy models include, but are not limited to, electrically-inducedcarotid arterial thrombosis, FeCl₃-induced carotid artery thrombosis andarteriovenous-shunt thrombosis. Models of kidney bleeding time, renalbleeding time and other bleeding time measurements can be used to assessthe bleeding risk of the antithrombotic agents described in the currentinvention.

ASSAYS Materials

1) PAR1 and PAR4 Agonist Peptides

SFFLRR is a known high affinity PAR1 selective agonist peptide.(Reference: Seiler, S. M., “Thrombin receptor antagonists”, Seminars inThrombosis and Hemostasis, 22(3):223-232 (1996).) The PAR4 agonistpeptides AYPGKF and H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂were synthesized. H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂showed improved PAR4 agonist activity over AYPGKF in the FLIPR assay(EC₅₀ value of 8 μM forH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and 60 μM for AYPGKF)and in washed platelet aggregation assay (EC₅₀ value of 0.9 μM forH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂ and 12 μM forAYPGKF).

2) PAR4 Expressing Cells

HEK293 cells stably expressing PAR4 were generated by a standard methodof transfection of human PAR4 (F2R23) cDNA expression vector andselected based on PAR4 protein expression or mRNA expression. Thosecells demonstrated functional responses to PAR4 agonist peptide-inducedintracellular calcium elevation using FLIPR® (Fluorometric Imaging PlateReader; Molecular Devices Corp.). These cells also express endogenousPAR1 and can elicit calcium signal upon stimulation with PAR1 agonistpeptide. Therefore, the same cells were also used to determineselectivity against PAR1 and agonist activity for both receptors. Cellsfrom HEK293 PAR4 Clone 1.2A (BMS Arctic ID 383940) were propagated andused for calcium mobilization studies.

3) Preparation of Platelet Rich Plasma (PRP)

Human blood was collected in 3.8% sodium citrate at a ratio of 1 ml per9 ml blood and centrifuged in a Sorvall® RT6000B centrifuge at 900revolution per minute (rpm) at room temperature (RT) for 15 minutes. PRPwas collected and used for aggregation assay. Refludan (Berlex Labs,Wayne, N.J.), a recombinant hirudin, at a final concentration of 1unit/mL was added to the sample to selectively prevent PAR1 activationinduced by residual alpha-thrombin contamination. The remaining bloodsample was centrifuged at 2500 rpm at room temperature for 5 minutes tocollect platelet-poor plasma (PPP).

4) Preparation of Washed Platelets (WP)

Human blood was collected in ACD (85 mM tri-sodium citrate, 78 mM citricacid, 110 mM D-glucose, pH 4.4) at a ratio of 1.4 ml per 10 ml blood.PRP was isolated by centrifugation at 170 g for 14 minutes and plateletswere further pelleted by centrifugation at 1300 g for 6 minutes.Platelets were washed once with 10 ml ACD containing 1 mg/ml bovineserum albumin. Platelets were resuspended at ˜2.5×10⁸/ml in Tyrode'sBuffer (137 mM NaCl, 2 mM KCl, 1.0 mM MgCl₂, 1 mM CaCl₂, 5 mM glucose,20 mM HEPES pH 7.4).

FLIPR Assay in PAR4-Expressing HEK293 Cells

FLIPR-based calcium mobilization assay in HEK293 cells was used tomeasure PAR4 antagonism, agonism, and selectivity against PAR1. Theactivity of the PAR4 antagonists of the present invention were tested inPAR4 expressing cells by monitoringH-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂-induced intracellularcalcium mobilization. Counter screens for agonist activity and PAR1antagonist activity were also performed. Briefly, PAR1/PAR4-expressingHEK293 cells were grown in DMEM (Life Technology, Grand Island, N.Y.)containing 10% heat-inactivated FBS, 1% Penicillin-Streptomycin, 10μg/mL blasticidin, and 100 μg/mL Zeocin at 37° C. with 5% CO₂. Cellswere plated overnight prior to the experiment in a black 384-wellPurecoat Amine clear bottom plate (Becton Dickinson Biosciences, SanJose, Calif.) at 10,000 cells/well in 30 μL growth medium and incubatedin a humidified chamber at 37° C. with 5% CO₂ overnight. Prior tocompound addition, the cell medium was replaced with 40 μL of 1× calciumand magnesium-containing Hank's Balanced Saline Solution (HBSS) (with 20mM HEPES) and 1:1000 diluted fluorescent calcium indicator (CodexBiosolutions, Gaithersburg, Md.). After a 30 minute incubation period at37° C. and a further 30 minute incubation and equilibration period atroom temperature, 20 μL test compound (diluted in 1×HBSS buffer) wasadded at various concentrations at 0.17% dimethyl sulfoxide (DMSO) finalconcentration. Changes in fluorescence intensity were measured using aFunctional Drug Screening System (FDSS, Hamamatsu, Japan) to determineagonist activities. The cells were then incubated for 30 minutes at roomtemperature followed by addition of 20 μL of agonist peptide forantagonist activity measurement. The PAR4 agonist peptide(H-Ala-Phe(4-F)-Pro-Gly-Trp-Leu-Val-Lys-Asn-Gly-NH₂) and the PAR1agonist peptide (SFFLRR) were routinely tested to ensure a properresponse at the EC₅₀ value in the assay (˜5 μM for PAR4 agonist peptideand −2 μM for PAR1 agonist peptide). Compound potency was derived from11-point concentration-response curves.

Gamma Thrombin Induced Platelet Aggregation Assays

The ability of the compounds of the current invention to inhibitplatelet aggregation induced by gamma-thrombin was tested in a 96-wellmicroplate aggregation assay format. Briefly, 90 μL of PRP or washedplatelets were pre-incubated for 5 minutes at 37° C. with 3-foldserially diluted test compound, which was prepared as a 100-fold stocksolution in dimethyl sulfoxide (DMSO). Aggregation was initiated byaddition of 10 μL of gamma-thrombin (Haematologic Technologies, Inc.Essex Junction, Vt.) at 50-100 nM final concentration, which wastitrated daily to achieve 80% platelet aggregation. The plate was thenplaced into a SpectraMax® Plus Plate Reader (Molecular Devices) at 37°C. Platelet aggregation was monitored at a wavelength of 405 nm using akinetic analysis mode. Prior to the first data collection time point,the plate was shaken for 10 seconds to allow thorough mixing. Data wassubsequently collected every 10 seconds for up to 7 minutes total. Datawas collected using SoftMax® 5.4.1 software and exported to MicrosoftExcel for analysis. The optical density (OD) values at the time pointthat achieved 75% platelet activation by agonist alone were used foranalysis. The OD value from a PRP sample without any treatment served asODmaximum, and the OD value from a PPP sample containing no plateletsserved as the ODminimum. Inhibition of platelet aggregation (IPA) wascalculated based on the formula: %IPA=(100-100*[ODcompound−ODminimum]/[ODmaximum−ODminimum]). The IC₅₀value of the test compound was calculated by fitting the % IPA values tothe one-site concentration response equation:Y=A+(B−A)/{1+(C/X){circumflex over ( )}D]}, using XLfit for 32 bitExcel® Version 2 Build 30 (ID Business Solutions Limited).

The aggregation assays were also employed to test the selectivity of thecompound against other platelet receptors by using SFFLRR for PAR1,collagen (Chrono-Log, Havertown, Pa.) for collagen receptors, ADP forP2Y1 and P2Y12 and U46619 (Cayman Chemical, Ann Arbor, Mich.) forthromboxane receptors.

Alpha-thrombin Induced Platelet Aggregation Assays

The ability of PAR4 antagonists to inhibit platelet aggregation inducedby alpha-thrombin can be tested using human washed platelets. Theantagonists are pre-incubated with washed platelets for 20 min.Aggregation is initiated by addition of 1.5 nM alpha-thrombin(Haematologic Technologies, Essex Junction, Vt.) to 300 μl of washedplatelets at stirring speed of 1000 rpm. Platelet aggregation ismonitored using an Optical Aggregometer (Chrono-Log, Havertown, Pa.) andthe area under the curve (AUC) at 6 min was measured. IC₅₀ values arecalculated using vehicle control as 0% inhibition.

Tissue Factor-Induced Platelet Aggregation Assay

The ability of PAR1 or PAR4 antagonists to inhibit platelet aggregationinduced by endogenous thrombin can be tested in a tissue factor drivenaggregation assay. Aggregation is initiated by addition of CaCl₂ andrecombinant human tissue factor, which results in the generation ofthrombin through activation of the coagulation pathway in the plasma.Anticoagulant agents such as corn trypsin inhibitor (HaematologicTechnologies, Essex Junction, Vt.) at 50 μg/ml and PEFABLOC® FG(Centerchem, Norwalk, Conn.) are also added to the sample to preventfibrin clot formation during the time of the study. Platelet aggregationis monitored using standard instrumentation including opticalaggregometer or impedance aggregometer.

The following table sets out the results obtained employing variouscompounds of the invention tested in the PAR4 FLIPR assay.

TABLE PAR4 FLIPR assay (IC50, Ex. No. nM) 1 29 2 11 3 240 4 17 5 880 6130 7 800 8 8.1 9 220 10 2.2 11 1700 12 2.0 13 3.5 14 6.8 15 38 16 80 1713 18 98 19 41 20 30 21 3.3 22 1.8 23 5.3 24 2.0 25 130 26 3.3 27 5.4 283.0 29 1.4 30 4.7 31 240 32 3.0 33 120 34 1.6 35 54 36 7.7 37 22 38 2.139 10 40 36 41 400 42 5.2 43 170 44 220 45 99 46 17 47 34 48 2.1 49 9.750 92 51 180 52 4.7 53 9.8 54 94 55 14 56 4.7 58 3.0 59 5.0 60 19 61 4362 100 63 2.9 64 7.4 65 31 66 28 67 2.9 68 120 69 36 70 34 71 160 72 1.073 2.3 74 9.3 75 14 76 2.1 77 130 78 39 79 2.2 80 21 81 1.5 82 280 83 1184 2.5 85 8.5 86 7.2 87 2.0 89 1.4 90 84 91 62 92 2.0 93 0.3 94 1.4 950.8 96 1.1 97 1.7 98 0.3 99 0.6 100 0.5 101 0.2 102 0.9 103 2.5 104 1.7105 8.1 106 1.6 107 2.8 108 1100 109 8.3 110 12 111 1.1 112 2.0 113 3.0114 1600 115 1.3 116 1.4 117 0.5 118 2.2 119 16 120 28 121 0.7 122 3.9123 1.5 124 1.8 125 2.0 126 1.2 127 8.3 128 2.2 129 3.2 130 460 131 890132 59 133 570 134 120 135 2200 136 29 137 29 138 33 139 3.9 140 21 14180 142 5.6 143 36 144 0.3 145 4.5 146 7.0 147 1.7 148 48 149 4.2 150 94151 2000 152 38 153 16 154 3.8 155 0.8 156 1.4 157 31 158 0.7 159 25 1601.2 161 0.7 162 270 163 0.5 164 0.5 165 1.2 166 2.8 167 4.5 168 2.0 1690.4 170 0.3 171 0.6 172 1.7 173 2.7 174 3.0 175 23 176 980 177 190 17813 179 18 180 2.7 181 1.2 182 22 183 0.6 184 2300 185 6.5 186 17 187 390188 580 189 140 190 1700 191 6.4 192 2.8 193 1.2 194 2.5 195 32 196 2.3197 1.3 198 0.6 199 2.5 200 1.6 201 1.3 202 0.9 203 4.1 204 3.1 205 51206 0.7 207 0.9 208 1.1 209 1.1 210 0.3 211 21 212 2.4 213 5.8 214 4.3215 2.9 216 160 217 18 218 2.5 219 5.5 220 2.6 221 21 222 1.0 223 10 22415 225 54 226 140 227 160 228 890 229 3.9 230 2.2 231 1.0 232 0.7 2330.4 234 1.4 235 2.2 236 140 237 170 238 1300 239 7.9 240 72 241 5.4 242120 243 1.2 244 2.0 245 92 246 140 247 19 248 19 249 6.9 250 31 251 17252 0.5 253 0.6 254 1.5 255 0.8 256 1.2 257 2.1 258 2.8 259 14 260 4.8261 1.2 262 0.8 263 0.8 264 8.3 265 6.8 266 2.2 267 0.8 268 0.9 269 3.6270 17 271 1.5 272 3.2 273 4.3 274 5.7 275 0.9 276 1.2 277 9.0 278 4.6279 18 280 4.3 281 3.6 282 1.1 283 1.9 284 5.9 285 16 286 0.5 287 8.5288 8.6 289 1.3 290 6.0 291 11 292 0.8 293 1.0 294 5.2 295 0.7 296 1.2297 5.7 298 2.1 299 10 300 0.9 301 15 302 3.2 303 0.9 304 2.3 305 1.0306 1.0 307 0.9 308 3.6 309 3.3 310 9.1 311 93 312 6.7 313 2.9 314 10315 3.3 316 4.9 317 4.5 318 7.8 319 7.3 320 3.4 321 3.1 322 5.1 323 15324 42 325 0.7 326 1.1 327 5.2 328 1.4 329 1.1 330 57 331 9.2 332 2.4333 1.7 334 29 335 2.5 336 5.5 337 0.7 338 2.0 339 1.6 340 1.5 341 15342 11 343 0.7 344 11 345 0.6 346 3.7 347 0.8 348 4.4 349 2.7 350 2.8351 2.7 352 390 353 22 354 1.2 355 17 356 2.1 357 6.7 358 270 359 170360 160 361 5.5 362 4.1 363 1700 364 19 365 2.5 366 550 367 12 369 13370 5.8 371 1.8 372 1.3 373 0.9 374 110 375 1.7 376 72 377 4.3 378 8.7379 1.7 380 2.3 381 1.4 382 1.3 383 590 384 18 385 2.3 386 7.8 387 1.5388 0.7 389 0.4 390 3.6 391 2.0 392 3.1 393 30 394 130 395 5.8 396 4.6397 210 398 8.6 399 3.9 400 2.0 401 2.7 402 3.7 403 1.7 404 2.2 405 1.9406 3.5 407 0.9 408 3.2 409 0.4 410 0.3 411 4.4 412 0.3 413 3.4 414 7.0415 3.1 416 32 417 11 418 1.3 419 2.0 420 2.2 421 1.8 422 2.2 423 4.2426 5.4 427 7.6 428 5.9 429 0.5 430 0.9 431 1.1 432 0.4 433 0.6 434 1.4435 0.9 436 1.5 437 4.9 438 1.9 439 0.9 440 0.8 441 0.9 442 0.8 443 0.6444 0.8 445 3.2 446 2.3 447 21 448 2.1 449 0.3 450 0.5 451 0.7 452 0.4453 0.6 454 1.3 455 0.8 456 0.7 457 0.4 458 0.5 459 0.9 460 0.9 461 0.4462 0.2 463 0.7 464 1.5 465 1.4 466 0.7 467 1.9 468 0.8 470 2.2 471 5.2472 4.6 473 3.4 474 11 475 4.8 476 10 477 3.0 478 9.1 479 1.4 480 3.4481 0.6 482 0.6 483 0.8 484 1.0 485 1.6 486 1.5 487 1.3 488 14 489 9.1490 5.1 491 0.4 492 7.4 493 21 494 1.8 495 15 496 1.9 497 1.3 498 1.3499 4.4 500 3.8 501 4.0 502 1.7 512 1.2 513 1.1 514 1.9 515 2.6 516 2.0517 1.1 518 13 519 16 520 77 521 24 522 20 523 2.6 524 84 525 2.3 5262.0 527 1.4 528 5.0 529 0.9 530 1.8 531 0.7 532 1.7 533 0.7 534 0.9 5355.2 536 4.9 539 6.5 540 3.0 541 3.4 542 1.6 543 1.3 544 34 545 1.5 54614 547 5.2 549 1.0 550 0.4 552 0.7 553 1.2 554 0.7 555 1.1 556 0.7 5570.7 558 1.5 559 0.9 560 1.4 561 53 562 1.6 563 2.8 564 3.7 565 3.0 5661.8 567 5.9 568 2.4 569 8.2 570 6.6 571 1.0 572 0.9 573 1.6 574 2.0 5750.6 576 1.2 577 1.0 578 5.8 579 3.3 580 1.1 581 4.1 582 5.3 589 0.8 59025 591 7.0 592 0.7 596 130 597 15 598 3.7 599 5.6 600 2.4 601 3.5 6026.4 603 2.1 604 17 605 0.7 606 0.4 607 0.2 608 0.5 609 1.9 610 4.3 6112.1 613 65 614 30 615 870 616 4200 618 3.8 621 8.0 622 350 623 320 6240.7 625 1.8 626 7.2 627 1400 628 1.4 629 2.2 630 1.4 631 5.3 632 10 6332.6 634 44 635 10 636 3.0 637 2.1 638 2.7 639 1.4 640 8.0 641 250 6424.6 643 5.3 644 21 645 4.9 646 3.8 647 19 648 3.0 649 7.4 650 5.6 6514.3 652 11 653 0.83 654 1.0 655 1.1 656 2.4 657 1.1 658 3.0 659 2.1 6602.0 661 55 662 77 663 7.0 664 0.9 665 1.7 666 1.1 667 5.6 668 7.3 6692.3 671 1.9 672 1.9 673 39 674 20 675 10 676 3.2 677 3.8 678 1.0 679 2.5680 0.8 681 0.4 682 0.9 683 0.7 684 0.7 685 1.7 686 9.9 687 0.9 688 4.5689 0.3 690 0.3 691 0.9 692 1.8 693 1.3 694 2.1 695 1.0 696 2.6 697 2.9698 17 699 1.1 700 0.9 701 2.7 702 4.3 708 2.6 709 0.4 710 1.8 711 2.4712 3.2 713 1.8 714 1.2 715 0.9 716 2.0 717 1.6 718 1.7 719 1.7 720 3.2721 2.6 722 1.4 723 2.4 724 2.1 725 0.8 726 1.2 727 1.7 728 2.4 729 2.8730 13 731 0.9 733 1.1 734 1.0 735 1.1 736 5.3 737 8.1 738 10 740 0.9741 2.1 747 2.4 748 2.9 749 4.3 750 1.1 751 4.7 752 14 753 12 754 0.3755 0.3 762 1.4 763 4.0 764 1.7 765 0.8 766 2.9 767 3.4 768 10 769 3.2770 1.9 771 6.3 772 1.5 773 11 774 1.2 775 0.8 776 2.5 777 8.6 778 3.4779 3.3 780 5.0 781 6.0 782 2.7 783 4.2 784 2.8 785 3.5 786 2.2 787 2.9788 3.1 789 2.4 790 4.4 791 2.3 792 11 793 24 794 10 795 0.8 796 1.3 7973.1 798 2.5 799 2.9 800 2.5 801 2.6 802 2.0 803 3.5 804 2.8 806 6.6 8072.6 808 2.0 809 54 810 6.9 811 1.5 812 7.0 813 1.0 814 7.2 815 6.4 81610 817 3.6 818 1.8 819 1.2 820 1.7 821 4.6 822 1.6 823 5.1 824 1.5 8258.0 826 1.9 827 6.2 828 0.7 829 0.6 830 1.6 831 2.2 832 2.5 833 1.6 8343.0 835 0.5 836 1.2 837 17

Methods of Preparation

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reaction mixtures are performed in a solventor solvent mixture appropriate to the reagents and materials employedand suitable for the transformations being effected. It will beunderstood by those skilled in the art of organic synthesis that thefunctionality present on the molecule should be consistent with thetransformations proposed. This will sometimes require a judgment tomodify the order of the synthetic steps or to select one particularprocess scheme over another in order to obtain a desired compound of theinvention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Wuts et al. (Greene's Protective Groups In OrganicSynthesis, 4th Edition, Wiley-Interscience (2006).

Compounds of Formula I of this invention can be obtained by palladiumcatalyzed cross coupling of aryl halides of Formula Ia withorganometallic species R₃-M as shown in Scheme 1.

Alternatively, compounds of Formula I can also be prepared frompalladium catalyzed cross coupling of arylboronic acids of Formula Ibwith halides R₃—X shown in Scheme 2.

One way to prepare the quinoxalines of Formula Ia and Ib is through thecondensation reaction of the diamine Ic with ketoaldehyde Id, as shownin Scheme 3. In general, the condensation will give two regioisomersthat may be separated by chromatography. Structure of Formula Ia can beconverted to boronic acid Ib via Suzuki-Miyaura reaction.

A regio specific synthesis of quinoxalines of Formula Ia and Ib is shownin Scheme 4. A properly protected ortho-nitro aniline Ie is alkylatedwith methyl bromoacetate to yield compound If. Deprotection of compoundIf and reduction of compound Ig should initiate cyclization to give riseto compound Ih. Compound Ih can be oxidized to quinoxaline-2-one ofFormula Ii, which can be converted to the intermediate Ij withoxophosphorus halides. The halides in compound Ij can be displaced witha nucleophile containing an R₁ group to compound Ia, and compounds ofFormula Ia can be converted to corresponding boronic acids of Formula Ibvia Suzuki-Miyaura reaction. Intermediate Ii could also be converted toIk by condensation reaction with sodium chlorodifluoroacetate in thepresence of a base such as K₂CO₃. The difluoroalkoxy may be displacedwith a nucleophile containing an R₁ group to compound Ia.

Compounds of Formula II of this invention can be obtained as shown inScheme 5. Compound IIa can be condensed with dicarbonyl IIb to givecompound IIc. Acid catalyzed cyclization provides the key bromide IId.Palladium catalyzed cross coupling reaction with an appropriate boronicacid furnishes compound II.

Compounds of Formula III of this invention can be obtained as shown inScheme 6. Compound IIIa can be condensed with dimethylacetal IIIb togive compound IIIc. Acid catalyzed cyclization and triflate formationprovides the key coupling partner IIId. Palladium catalyzed crosscoupling reaction with an appropriate boronic acid furnishes thecompound of Formula III

Compounds of Formula IV of this invention can be obtained as shown inScheme 7. Compound IVa can be condensed with dimethylacetal IVb to givecompound IVc. Acid catalyzed cyclization and triflate formation providesthe key coupling partner IVd. Palladium catalyzed cross couplingreaction with an appropriate boronic acid furnishes the compound ofFormula IV.

Compounds of Formula V of this invention can be obtained as shown inScheme 8. Compound Va can be condensed with acid chloride Vb to givecompound Vc. Acid catalyzed cyclization and carbonyl alkylation providesthe key bromide Vd. Palladium catalyzed cross coupling reaction with anappropriate boronic acid furnishes the compound of Formula V.

Compounds of Formula VI of this invention can be obtained as shown inScheme 9. Compound VIa can be condensed with dicarbonyl compound VIb togive compound VIc. Palladium catalyzed cross coupling reaction with anappropriate boronic acid furnishes the compound of Formula VI.

In this invention, compounds of Formula VII can be obtained through thesynthetic route shown in Scheme 10. Beginning with aryl chloride VIIa,palladium catalyzed cross coupling of various boronic acids or stannanesyields substituted anilines of structure VIIb. Nitration of compoundVIIb and reduction of compound VIIc allows access to compounds ofFormula VIId. Base mediated condensation of dianiline VIId withsubstituted bromo-ketones provides heterocycles of Formula VIIe. A finalpalladium-catalyzed cross coupling with aryl boronic acids or stannanesthen furnishes the compounds of Formula VII.

Compounds of Formula VIII of this invention can be obtained by palladiumcatalyzed cross coupling of aryl boronic acids or stannanes with arylchloride VIIIc as shown in Scheme 11. Compound Villa can be condensedwith amidines to give compound VIIIb. Phosphorous oxychloride conversionof compound VIIIb to aryl chloride VIIIc followed by palladium-catalyzedcross coupling with aryl boronic acids or stannanes furnishes thecompound of Formula VIII.

A synthesis of 2-halo benzothiazole XXI is shown in Scheme 12. Beginningwith the appropriately substituted aniline XIX, the 2-aminobenzothiazole XX is formed via addition and oxidative cyclization of athiocyanate. Subsequent Sandmeyer chemistry is employed to generate thedesired 2-halo benzothiazole XXI. With XXI in hand, various compounds ofFormula I with structure XXIIa are prepared with boronic acid Ib viaSuzuki cross-coupling. Intermediates for preparation of compounds ofFormulas I-VIII containing bicyclic R₃ groups other than benzothiazoleare commercially available or can be prepared by one skilled in the art,and can be incorporated into compounds of Formulas I-VIII via crosscoupling chemistry as shown in Scheme 12.

When compounds of structure XXIIb are used as a starting material,several compounds of Formula I with structure XXIII are prepared througheither alkylation or Mitsunobu chemistry as shown in Scheme 13.Compounds XXIVa are accessed via epoxide opening of a variety ofmono-substituted epoxides, and compounds XXIVb are accessed through theopening of di-substituted cyclic sulfates.

Substitution at the 4-position of the benzothiazole R₃ group can beaccomplished from intermediates XXVa and XXVb as shown in Scheme 14.Lithiation of XXVa followed by its addition to a variety of aldehydesprovides XXVI, as does Grignard addition to benzaldehyde XXVb. XXVI isthen coupled to Ib as described above to provide compounds of Formula Iwith structure XXVII.

Many compounds derived from the core structures depicted above can beeither acylated or sulfonylated using the strategy shown in Scheme 15.Thus, chloroformate XXIX is synthesized from compounds with formulasanalogous to XXVIII using phosgene. These chloroformates are thenreacted with a variety of nucleophiles to generate compounds ofstructure XXX. Compounds of structure XXXII are synthesized from aminessuch as XXXI using sulfonyl chloride reagents.

General Methods

The following methods were used in the exemplified Examples, exceptwhere noted otherwise.

Products were analyzed by reverse phase analytical HPLC carried out on aShimadzu Analytical HPLC system running Discovery VP software using oneof the following methods

Method A: PHENOMENEX® Luna C18 column (4.6×50 mm or 4.6×75 mm) eluted at4 mL/min with 2, 4 or 8 min gradient from 100% A to 100% B (A: 10%methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA,UV 220 nm).

Method B: PHENOMENEX® Luna C18 column (4.6×50 mm) eluted at 4 mL/minwith a 4 min gradient from 100% A to 100% B (A: 10% acetonitrile, 89.9%water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).

Method C: PHENOMENEX® Luna C18 column (4.6×50 mm or 4.6×75 mm) eluted at4 mL/min with a 2, 4 or 8 min gradient from 100% A to 100% B (A: 10%methanol, 89.9% water, 0.1% H₃PO₄; B: 10% water, 89.9% methanol, 0.1%H₃PO₄, UV 220 nm).

Method D: PHENOMENEX® Luna C18 column (4.6×50 mm or 4.6×75 mm) eluted at4 mL/min with a 2, 4 or 8 min gradient from 100% A to 100% B (A: 10%methanol, 89.9% water, 0.1% NH₄OAc; B: 10% water, 89.9% methanol, 0.1%NH₄OAc, UV 220 nm).

Method E: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05%TFA; wavelength 220 nm; flow rate 0.8 mL/min; 0% B to 100% B in 1minute, gradient time 1.5 min.

Method F: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05%TFA; wavelength 220 nm; flow rate 0.8 mL/min; 0% B to 50% B in 1 minute,gradient time 1.5 min.

Method G: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05%TFA; wavelength 220 nm; flow rate 0.8 mL/min; 50% B to 100% B in 1minute, gradient time 1.5 min.

Reverse phase preparative HPLC was carried out using a ShimadzuPreparative HPLC system running Discovery VP software using one of thefollowing methods.

Method A: PHENOMENEX® Axia Luna 5 μM C18 30×75 mm column with a 10 mingradient at 40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9%water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).

Method B: YMC Sunfire 5 μM C18 30×100 mm column with a 10 min gradientat 40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1%TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).

Method C: XBridge C18, 19×200 mm column, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B:95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Flow: 20 mL/min.

Method D: Waters XBridge C18, 19×100 mm column, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Flow: 20mL/min.

Method E: PHENOMENEX® Luna 5 μM C18 30×100 mm column with a 10 mingradient at 40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9%water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).

Method F: PHENOMENEX® Luna 5 μM C18 30×100 mm column with a 10 mingradient at 40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9%water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).

Method G: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A:5:95 acetonitrile:water with 0.1% formic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% formic acid; Flow: 20 mL/min.

LCMS chromatograms were obtained on a Shimadzu HPLC system runningDiscovery VP software, coupled with a Waters ZQ mass spectrometerrunning MassLynx version 3.5 software using

Method A: A linear gradient using solvent A (10% acetonitrile, 90%water, 0.1% of TFA) and solvent B (90% acetonitrile, 10% water, 0.1% ofTFA); 0-100% of solvent B over 2 min and then 100% of solvent B over 1min. Column: PHENOMENEX® Luna 3 u C18(2) (2.0×30 mm). Flow rate was 5ml/min. And UV detection was set to 220 nm. The LC column was maintainedat room temperature.

Method B: A linear gradient using solvent A (10% methanol, 90% water,0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA);0-100% of solvent B over 4 min and then 100% of solvent B over 1 min.Column: PHENOMENEX® Luna 5 u C18 (4.5×30 mm). Flow rate was 4 ml/min.And UV detection was set to 220 nm. The LC column was maintained at roomtemperature.

Method C: A linear gradient using solvent A (10% methanol, 90% water,0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA);0-100% of solvent B over 2 min and then 100% of solvent B over 1 min.Column: PHENOMENEX® Luna 3 u C18(2) (2.0×30 mm). Flow rate was 1 ml/min.And UV detection was set to 220 nm. The LC column was maintained at roomtemperature.

Method D: A linear gradient using solvent A (10% methanol, 90% water,0.1% of TFA) and solvent B (90% methanol, 10% water, 0.1% of TFA);0-100% of solvent B over 2 min and then 100% of solvent B over 1 min.Column: PHENOMENEX® Luna 3 u C18(2) (4.5×30 mm). Flow rate was 5 ml/min.And UV detection was set to 220 nm. The LC column was maintained at roomtemperature.

Method E: 30-95% acetonitrile in water with 0.1% TFA in 8 min run,Waters Xbridge 4.6×50 mm 5 um C18, flow rate 1.2 mL/min and UV detectionwas set to 220 nm. The LC column was maintained at room temperature.

Method F: 10-95% methanol in water, 0.1% TFA in a 10 min run,PHENOMENEX® Onyx Monolithic 4.6×100 mm 5 um C18, flow rate 2.0 mL/mL andUV detection was set to 220 nm. The LC column was maintained at roomtemperature.

Method G: 5-95% acetonitrile in water, 10 mM of modifier in 6 min run,Waters Xbridge 2.1×50 mm 5 um C18, flow rate 1.0 mL/min and UV detectionwas set to 220 nm. The LC column was maintained at room temperature.

Method H: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05%TFA; wavelength 220 nm; flow rate 0.8 mL/min; gradient time 1.5 min; 2to 98% B.

Method I: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05%TFA; wavelength 220 nm; flow rate 0.8 mL/min; gradient time 1.5 min; 2to 52% B.

Method J: BEH C18 2.1×50 mm; A: water+0.05% TFA; B: acetonitrile+0.05%TFA; wavelength 220 nm; flow rate 0.8 mL/min; gradient time 1.5 min; 48to 98% B.

Method K: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

Method L: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0-100% B over 3minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min;Detection: UV at 220 nm.

In addition, the following orthogonal HPLC conditions were used to checkthe purity of the compounds

Method A: Two analytical LC/MS injections were used to determine thefinal purity. Injection1 condition: A linear gradient using solvent A(5% acetonitrile, 95% water, 0.05% TFA) and solvent B (95% acetonitrile,5% water, 0.05% TFA); 10-100% of solvent B over 10 min and then 100% ofsolvent B over 5 min. Column: Sunfire C18 3.5 um (4.6×150 mm). Flow ratewas 2 ml/min. And UV detection was set to 220 nm. The LC column wasmaintained at room temperature. Injection 2 conditions: A lineargradient using solvent A (5% acetonitrile, 95% water, 0.05% TFA) andsolvent B (95% acetonitrile, 5% water, 0.05% TFA); 10-100% of solvent Bover 10 min and then 100% of solvent B over 5 min. Column: XbridgePhenyl 3.5 um (4.6×150 mm). Flow rate was 2 ml/min. And UV detection wasset to 220 nm. The LC column was maintained at room temperature.

Method B: Two analytical LC/MS injections were used to determine thefinal purity. Injection 1 conditions: Column: Waters Acquity UPLC BEHC18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B;Flow: 1.11 mL/min; Detection: UV at 220 nm. Injection 2 conditions:Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

General Procedures

The following procedures were used during the synthesis of the Examplesand Intermediates where indicated below.

Procedure A: 5-bromo-2-chloropyrimidine (1.0 equiv.) was solvated in DMF(0.2 M) along with the appropriate diol (2.0 equiv.). 60% sodium hydridein mineral oil (3.0 equiv.) was added to the reaction mixtureportion-wise at 0° C., then the reaction mixture allowed to warm to roomtemperature and stirred for 30 minutes. The reaction mixture was thenquenched with saturated ammonium chloride and diluted with EtOAc. Theorganic layer was washed with 10% aqueous LiCl solution (3×), brine(1×), dried with sodium sulfate, filtered and concentrated. Theresulting residue was dissolved in methylene chloride before beingpurified by silica gel chromatography to provide the desired material.

Procedure B: To a vial containing the appropriate 5-bromopyrimidine (1.0equiv.), palladium(II) acetate (0.1 equiv.), BINAP (0.2 equiv.), cesiumcarbonate (1.2 equiv.) and diphenylmethanimine (1.1 equiv.) was addedtoluene (0.5 M). The vial was sealed, evacuated and backfilled with Ar3×, and the reaction mixture was heated to 105° C. for 18 hours. Thereaction mixture was then diluted with EtOAc and washed with 1M aqueousNaOH (1×) and brine (1×). The organic layer was dried with sodiumsulfate, filtered and concentrated. The resulting residue was dissolvedin methylene chloride before being purified by silica gel chromatographyto provide the desired material.

Procedure C: The 4-((diphenylmethylene)amino)pyrimidine intermediate(1.0 equiv.) was dissolved in 1:1 MeOH/THF (0.06M). 1M aqueous HCl (2.5equiv.) was added to the reaction mixture at room temperature. Thereaction mixture was allowed to stir at room temperature for 1 hour thendiluted with water and extracted with 5:1 EtOAc/Hexanes (3×). Theaqueous phase was concentrated and azeotroped with toluene 3× to yieldthe desired 4-aminopyrimidine which was brought forward without furtherpurification.

Procedure D: 4-bromo-2-fluoropyridine (1.0 equiv.) was dissolved in DMF(1.1 M) along with the appropriate diol (1.5 equiv.). 60% sodium hydridein mineral oil (2.0 equiv.) was added to the reaction mixtureportion-wise at 0° C. and the reaction mixture was allowed to warm toroom temperature and stirred at room temperature for 4 hours. Thereaction mixture was then quenched with saturated ammonium chloridesolution and extracted with EtOAc (3×). The organic layer was washedwith brine, dried with sodium sulfate, filtered and concentrated. Theresulting residue was dissolved in methylene chloride before beingpurified by silica gel chromatography to provide the desired material.

Procedure E: N1,N2-dimethylethane-1,2-diamine (1.0 equiv.),2,2,2-trifluoroacetamide (2.0 equiv.), copper(I) iodide (0.2 equiv.),potassium carbonate (2.0 equiv.) and the 4-boromo-2-alkoxypyridineintermediate (1.0 equiv.) were dissolved in dioxane (0.6 M) in a sealedvial. The vial was evacuated and backfilled with Ar 3× then the reactionmixture was stirred at 75° C. for 2 hours. 3 mL of 1:1 MeOH/H₂O wasadded to the mixture which was stirred at room temperature for 2 h thenat 40° C. for 1 h. The reaction mixture was then diluted with water andextracted with EtOAc (3×). The combined organic layer was washed withbrine, dried with sodium sulfate, filtered and concentrated. Theresulting residue was dissolved in a small amount of methylene chloridebefore being purified by silica gel chromatography to provide thedesired material.

Procedure F: The ester (1.0 equiv.) was dissolved in THF (0.2 M) and thesolution was cooled to −78° C. 1M DIBAL-H in toluene (3.0 equiv.) wasadded to the mixture which was allowed to warm to room temperature andstirred at room temperature for 30 minutes. The reaction mixture wasthen quenched saturated Rochelle's salt and allowed to stir for 18 h atroom temperature. The mixture was then diluted with water and extractedwith EtOAc (3×). The combined organic layer was washed with brine (1×),dried with sodium sulfate, filtered and concentrated yield the desiredproduct.

Procedure G: The ester (1.0 equiv.) was dissolved in THF (0.2 M) andcooled to −78° C. To the cooled reaction mixture was added 1M DIBAL-H intoluene (3.0 equiv.) and the reaction mixture was allowed to stir at−78° C. for 1 hour. The reaction mixture was then quenched saturatedRochelle's salt and allowed to stir for 2 h at room temperature. Themixture was then diluted with water and extracted with EtOAc (3×). Thecombined organic layer was washed with brine (1×), dried with sodiumsulfate, filtered and concentrated. The resulting aldehyde intermediatewas then re-subjected to the conditions described above to ultimatelyyield the desired alcohol product.

Procedure H: To the ester (1.0 equiv.) dissolved in THF (0.06 M) at −78°C. was added methylmagnesium bromide (10.0 equiv.). The reaction mixturewas allowed to warm to room temperature and stirred for 30 minutes atroom temperature. The reaction mixture was then quenched with saturatedammonium chloride, diluted with water and extracted with EtOAc (3×). Thecombined organic layer was washed with brine (1×), dried with sodiumsulfate, filtered and concentrated. The resulting residue was purifiedby reverse phase preparative HPLC to yield the desired product.

Procedure I: The alcohol (1.0 equiv.), imidazole (2.2 equiv.) and TBS-Cl(2.0 equiv.) were dissolved in THF or DCM (0.1 M). The reaction mixturewas allowed to stir at room temperature for 18 h. The reaction mixturewas then diluted with 1.5 M dipotassium phosphate solution and extractedwith EtOAc (3×). The combined organic layer was washed with brine (1×),dried with sodium sulfate, filtered and concentrated. The resultingresidue was dissolved in a small amount of methylene chloride andpurified by silica gel chromatography to yield the desired product.

Procedure J: The silyl protected intermediate (1.0 equiv.) was dissolvedin a mixture of 20:1 MeOH/concentrated aqueous HCl (0.01 M), and thereaction mixture was stirred at room temperature. The reaction wasmonitored by LCMS, and after completion of the reaction (10 min-12hours) the reaction mixture was concentrated, dissolved in DMF andpurified by preparative HPLC to yield the desired example.

Procedure K: The acetonide intermediate (1.0 equiv.) was dissolved in amixture of 4:3:2 THF/MeOH/concentrated aqueous HCl (0.01 M), and thesolution was stirred at room temperature. The resulting mixture wasmonitored by LCMS, and after completion of the reaction (10 min-12hours) the mixture was diluted with EtOAc, washed with 1.5 M K₂HPO₄,dried over sodium sulfate, filtered, concentrated, dissolved in DMF andpurified by preparative HPLC to yield the desired example.

EXAMPLES

The invention is further defined in the following Examples. It should beunderstood that the Examples are given by the way of illustration only.From the above discussion and the Examples, one skilled in the art canascertain the essential characteristics of the invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications to adapt the invention to various uses and conditions.As a result, the invention is not limited by the illustrative examplesset forth herein below, but rather is defined by the claims appendedhereto.

ABBREVIATIONS

-   AcOH acetic acid-   ACN acetonitrile-   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthylene-   Boc tert-butoxycarbonyl-   BOC₂O di(tert-butoxycarbonyl) ether-   BuLi butyl lithium-   DCE dichloroethane-   DCM dichloromethane-   DIAD diisopropyl azodicarboxylate-   DIBAL-H diisobutylaluminium hydride-   DIEA diisopropylethylamine-   DMAP dimethylaminopyridine-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   EtOAc ethyl acetate-   EtOH ethanol-   HOBt hydroxybenzotriazole-   mCPBA 3-chloroperbenzoic acid-   MeCN acetonitrile-   MeOH methanol-   NH₄OAc ammonium acetate-   NMP N-methylpyrrolidinone-   PdCl₂(dppf)-CH₂Cl₂    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),    dichloromethane adduct-   Pd(OAc)₂ palladium acetate-   Pd(Ph₃P)₄ tetrakis(triphenylphosphine)palladium-   TBAF tetrabutylammonium fluoride-   TBDMS-Cl tert-butyldimethylsilyl chloride-   TEA triethylamine-   TFA trifluoroacetate-   THF tetrahydrofuran-   HPLC high pressure liquid chromatography-   MS mass spectrometry-   g gram(s)-   h or hr hour(s)-   min. minute(s)-   mL milliliter(s)-   mmol millimole(s)-   RT retention time

INTERMEDIATE I-12-(difluoromethoxy)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

Intermediate I-1A: tert-butylN-(2-bromo-4-methyl-6-nitrophenyl)-N-[(tert-butoxy) carbonyl]carbamate

To a solution of 2-bromo-4-methyl-6-nitroaniline (9.6 g, 41.6 mmol) inTHF (60 mL) was added DMAP (0.508 g, 4.16 mmol), followed by BOC₂O(22.67 g, 104 mmol) as a solid. The mixture was stirred at roomtemperature overnight. Solvent was removed by vacuum. The crude productwas dissolved in a small amount of chloroform and charged to a 120 gsilica gel cartridge (2 separate columns) which was eluted with 5% EtOAcin hexanes for 4 min., then a 12 min gradient from 5% to 30% EtOAc inhexanes. The desired fractions were combined and concentrated to giveIntermediate I-1A (17.12 g, 39.7 mmol, 96% yield) as a white solid. ¹HNMR (500 MHz, chloroform-d) δ 7.80-7.79 (m, 1H), 7.73 (dd, J=1.9, 0.8Hz, 1H), 2.48 (s, 3H), 1.42 (s, 18H); LC-MS: method A, RT=1.90 min, MS(ESI) m/z: 230.0 and 232.0 (M-2 Boc)⁺.

Intermediate I-1B: tert-butyl (2-bromo-4-methyl-6-nitrophenyl)carbamate

To a solution of Intermediate I-1A (17.1 g, 39.6 mmol) indichloromethane (60 mL) was added TFA (6.11 mL, 79 mmol) and the mixturewas stirred at room temperature for 1.0 h. The reaction mixture wasquenched by addition of saturated sodium bicarbonate, extracted withdichloromethane (3×), dried over sodium sulfate. After evaporation ofsolvent, Intermediate I-1B was obtained as a yellow solid (12.88 g, 88%yield): ¹H NMR (500 MHz, chloroform-d) δ 7.71 (d, J=1.1 Hz, 1H), 7.68(dd, J=1.9, 0.8 Hz, 1H), 2.42 (s, 3H), 1.51 (s, 9H); LC-MS: method A,RT=1.53 min, MS (ESI) m/z: 231.0 and 233.0 (M-Boc)⁺.

Intermediate I-1C: methyl2-((2-bromo-4-methyl-6-nitrophenyl)(tert-butoxycarbonyl) amino)acetate

Intermediate I-1B (12 g, 26.3 mmol) was dissolved in DMF (80 mL), cooledwith a water bath. Cs₂CO₃ (25.8 g, 79 mmol) was added. The dark brownsolution was stirred at room temperature for 10 min, then methyl2-bromoacetate (4.37 mL, 47.6 mmol) was added dropwise. After additionof methyl bromoacetate, the brown color faded to yellow. The mixture wasstirred at room temperature for 1.0 h, diluted with EtOAc, quenched withwater. The organic layer was collected, washed with brine, dried oversodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 330 g silicagel cartridge which was eluted with 5% EtOAc in hexanes for 5 min., thena 12 min gradient from 5% to 50% EtOAc in hexanes. The desired fractionswere combined and concentrated to give Intermediate I-1C (15.2 g, 37.7mmol, 95% yield) as an yellow oil. ¹H NMR (500 MHz, chloroform-d)indicated a mixture of rotamers: δ 7.75-7.67 (m, 2H), 4.61-3.97 (m, 2H),3.76 and 3.69 (s, 3H), 2.48 and 2.43 (s, 3H), 1.55 and 1.37 (s, 9H);LC-MS: method A, RT=1.70 min, MS (ESI) m/z: 303.0 and 305.0 (M-Boc)⁺.

Intermediate I-1D: methyl2-((2-bromo-4-methyl-6-nitrophenyl)amino)acetate

To Intermediate I-1C (15.2 g, 37.7 mmol) was added 4.0 N HCl in dioxane(47.1 ml, 188 mmol) and the mixture was stirred at room temperatureovernight. Solvent was removed under vacuum, chased with EtOAc (2×) togive Intermediate I-1D (13.6 g, 40.1 mmol, 106% yield) as a yellowsolid. ¹H NMR (500 MHz, methanol-d₄) δ 7.88 (dd, J=1.9, 0.6 Hz, 1H),7.80 (dd, J=1.9, 0.6 Hz, 1H), 4.47 (d, J=17.3 Hz, 1H), 4.08 (d, J=17.1Hz, 1H), 3.69 (s, 3H), 2.46 (s, 3H); LC-MS: Method A, RT=1.94 min, MS(ESI) m/z: 303.1 and 305.1 (M+H)⁺.

Intermediate I-1E: 5-bromo-7-methyl-3,4-dihydroquinoxalin-2(1H)-one

To a solution of Intermediate I-1D (13.6 g, 40.1 mmol) in MeOH (100 mL)in a 1 L flask cooled with water bath was added concentrated HCl (13.35mL, 160 mmol), followed by tin(II) chloride dihydrate (36.1 g, 160mmol). The mixture was stirred at 68° C. for 2.5 h. MeOH was removed byvacuum. The crude was partitioned in water (100 mL)/EtOAc (200 mL), andthe pH was adjusted to neutral with 4.0 N NaOH (ca 90 mL). The whiteprecipitate formed was very fine particle that was very hard to removeby filtration. The mixture was transferred to a separatory funnel. Theorganic layer was collected. The aqueous was further extracted (2×200mL) with EtOAc. The combined organic layer was washed with water (2×)and brine (2×), dried over sodium sulfate. After evaporation of solvent,Intermediate I-1E (8.36 g, 34.7 mmol, 87% yield) was obtained as a paleyellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.37 (s, 1H), 6.87 (dd,J=1.8, 0.7 Hz, 1H), 6.56 (dd, J=1.1, 0.6 Hz, 1H), 5.46 (s, 1H), 3.76 (d,J=2.2 Hz, 2H), 2.14 (s, 3H); LC-MS: method A, RT=1.66 min, MS (ESI) m/z:241.0 and 243.0 (M+H)⁺.

Intermediate I-1F: 5-bromo-7-methylquinoxalin-2-ol

To a suspension of Intermediate I-1E (6.7 g, 27.8 mmol) in MeOH (50 mL)in a 1 L flask was added 30% hydrogen peroxide (28.4 mL, 278 mmol),followed by 4.0 N NaOH (20.84 mL, 83 mmol). The mixture was stirred atroom temperature for 5 min, then gently heated at 60° C. After 15 minheating, the reaction mixture turned strongly exothermic, suggesting aninitiation of the reaction mixture. The heating bath was removed andstirring continued for 30 min until the mixture turned completely clear.After cooling to room temperature with a water bath, MeOH was removed byvacuum. The mixture was then neutralized with 2.0 N HCl (to pH 2-3) andice cooling. The precipitate formed was collected by filtration, washedwith water, dried under vacuum in the air for 1.0 h and then at vacuumat 60° C. for 2.0 h, and under high vacuum to give Intermediate I-1F(6.55 g, 27.4 mmol, 99% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 12.52 (br. s., 1H), 8.17 (s, 1H), 7.49 (d, J=1.1 Hz, 1H),7.08 (s, 1H), 2.40 (s, 3H; LC-MS: method A, RT=1.62 min, MS (ESI) m/z:239.0 and 241.0 (M+H)⁺.

Intermediate I-1G: 5-bromo-2-(difluoromethoxy)-7-methylquinoxaline

A mixture of Intermediate I-1F (7.4 g, 26.9 mmol) and potassiumcarbonate (18.56 g, 134 mmol) in DMF (120 mL) was heated at 100° C. for5 min. Sodium 2-chloro-2,2-difluoroacetate (16.40 g, 107.6 mmol) wasadded in one portion, and the mixture was stirred at 100° C. for 10 min.The mixture turned from yellow slurry to brown. The mixture was cooledto room temperature, diluted with EtOAc and water, extracted with EtOAc(3×). The combined organic layer was washed with brine, dried oversodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform/toluene and purified with a330 g ISCO column eluted with 5% dichloromethane in hexanes for 3 min,then 5-70% DCM/hexanes for 40 min (12 min gradient time). The desiredfractions were combined, concentrated to give Intermediate I-1G (6.0 g,20.76 mmol, 77% yield) as a slightly yellow solid. ¹H NMR (500 MHz,chloroform-d) δ 8.64 (s, 1H), 7.89 (d, J=1.7 Hz, 1H), 7.68 (dd, J=1.8,1.0 Hz, 1H), 7.63 (t, J_(HF)=71.80 Hz, 1H), 2.59 (s, 3H); ¹⁹F NMR (471MHz, chloroform-d) δ −89.82 (s, 2F); LC-MS: method A, RT=2.09 min, MS(ESI) m/z: 289.0 and 291.0 (M+H)⁺.

Intermediate I-1

A mixture of Intermediate I-1G (1.04 g, 3.60 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.370 g,5.40 mmol), potassium acetate (0.883 g, 8.99 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (0.147 g, 0.180 mmol) in dioxane (14 mL) wasdegassed by bubbling argon for 10 min. The reaction mixture vial wassealed and heated in microwave reactor at 135° C. for 30 min. Themixture was diluted with EtOAc/water, insoluble material was removed byfiltration. The filtrate was extracted with EtOAc, washed with brine anddried over sodium sulfate. After evaporation of solvent, the crudeproduct was dissolved in a small amount of toluene and charged to a 40 gsilica gel cartridge which was eluted with 5% EtOAc in hexanes for 2min., then a 18 min gradient from 5% to 75% EtOAc in hexanes. Thedesired fractions were concentrated and lyophilized to give IntermediateI-1 (0.93 g, 72% yield) as a pale solid. ¹H NMR was complicated by thepresence of two sets of signals. ¹⁹F NMR indicated a single compound.¹⁹F NMR (471 MHz, chloroform-d) δ −89.64 (s., 2F). LC-MS: method A,RT=2.01 min, MS (ESI) m/z: 225.0 (boronic acid)⁺.

Intermediate I-22-(methoxymethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

Intermediate I-2A: 1-diazo-3-methoxypropan-2-one

To 2-methoxyacetyl chloride (2.4 g, 22.12 mmol) in MeCN (40 mL) cooledwith ice-bath was added (diazomethyl)trimethylsilane 2.0 M in diethylether (19.35 mL, 38.7 mmol). The mixture was allowed to stir at roomtemperature overnight. Solvent was removed under reduced pressure. Thecrude product was purified by flash chromatography (loading inchloroform, 0% to 50% EtOAc in hexane over 18 min using a 40 g silicagel cartridge). The desired fractions were combined and concentrated(bath temp below 35° C.) to yield Intermediate I-2A (1.82 g, 15.95 mmol,72.1% yield) as a yellow liquid. ¹H NMR (500 MHz, chloroform-d) δ 5.73(br. s., 1H), 3.97 (br. s., 2H), 3.43 (s, 3H); LC-MS: method A, RT=0.43min, MS (ESI) m/z: 137.0 (M+Na)⁺.

Intermediate I-2B: 1-bromo-3-methoxypropan-2-one

To Intermediate I-2A (1.6 g, 14.02 mmol) in diethyl ether (20 mL) at 0°C. was added aqueous HBr 48% (2.380 mL, 21.03 mmol) dropwise. Afterstirring at 0° C. for 5 min and at room temperature for 10 min, thereaction mixture was diluted with EtOAc, washed with water, saturatedsodium bicarbonate (2×) and brine. The organic layer was dried oversodium sulfate, concentrated (keep bath temp below 30° C.) to giveIntermediate I-2B (1.5 g, 8.98 mmol, 64.1% yield) as a slightly yellowliquid. ¹H NMR indicated >92% purity. The compound was used immediatelyfor the next step without further purification. ¹H NMR (500 MHz,chloroform-d) δ 4.24 (s, 2H), 4.03 (s, 2H), 3.45 (s, 3H), consistentwith literature report (I Org. Chem. 1981, 217).

Intermediate I-2C: tert-butyl(2-bromo-4-methyl-6-nitrophenyl)(3-methoxy-2-oxopropyl)carbamate

To Intermediate I-1B (1.98 g, 5.98 mmol) in DMF (20 mL) at 0° C. wasadded Cs₂CO₃ (3.41 g, 10.46 mmol). The brown solution was stirred at 0°C. for 10 min, followed by addition of Intermediate I-2B (1.498 g, 8.97mmol) in acetonitrile (5.0 mL). The brown solution turned yellow. Themixture was stirred at 0° C. for 15 min., diluted with EtOAc, washedwith water, brine, dried over sodium sulfate and concentrated. The crudeproduct was purified by flash chromatography (loading in chloroform, 0%to 60% EtOAc in hexane over 18 min using a 80 g silica gel cartridge).The desired fractions were combined and concentrated to yieldIntermediate I-2C (2.4 g, 5.75 mmol, 96% yield) as a yellow oil. ¹H NMRindicated presence of two rotamers. ¹H NMR (500 MHz, chloroform-d) δ7.70-7.65 (m, 2H), 4.55 (d, J=17.9 Hz, 1H), 4.18 (d, J=17.9 Hz, 1H),4.32 and 4.14 (d, J=1.4 Hz, 2H), 3.44 and 3.40 (s, 3H), 2.45 and 2.40(s, 3H), 1.49 and 1.35 (s, 9H); LC-MS: method A, RT=1.89 min, MS (ESI)m/z: 317 and 319 (M-Boc)⁺.

Intermediate I-2D6-bromo-3-hydroxy-3-(methoxymethyl)-8-methyl-1-oxo-1,3,4,5-tetrahydrobenzo[c][1,2,5]oxadiazepin-1-ium

To Intermediate I-2C (1.67 g, 4.00 mmol) in ethyl acetate (10 mL) wasadded 4.0 N HCl in dioxane (10.01 mL, 40.0 mmol) and the mixture wasstirred at room temperature for 20 min. Solvent was removed undervacuum, chased with EtOAc once to give Intermediate I-2D (1.25 g, 99%)as a yellow oil. ¹H NMR (400 MHz, chloroform-d) δ 7.75-7.66 (m, 2H),4.13-3.98 (m, 1H), 3.78-3.56 (m, 3H), 3.50 and 3.44 (m, 3H), 2.39 (s,3H); LC-MS: method A, RT=1.47 min, MS (ESI) m/z: 317.0 and 319.0 (M+H)⁺.

Intermediate I-2E: 5-bromo-2-(methoxymethyl)-7-methylquinoxaline

Intermediate I-2D (1.25 g, 3.9 mmol) was dissolved in THF (30 mL).Concentrated HCl (0.986 mL, 12.01 mmol) was added, followed by tin(II)chloride dihydrate (3.61 g, 16.01 mmol). The mixture was placed andstirred in an oil bath pre-heated at 40° C. for 4.0 h. The reactionmixture was diluted with EtOAc/water, The organic phase was neutralizedwith saturated sodium bicarbonate and stirred at room temperature for 15min, the precipitate was removed by filtration with a pad of wet celite.The filtrate was collected. The organic layer was washed with brine,dried over sodium sulfate and concentrated. The crude product waspurified by flash chromatography (loading in chloroform, 0% to 60% EtOAcin hexane over 20 min using a 120 g silica gel cartridge). The desiredfractions were combined and concentrated to yield Intermediate I-2D(0.57 g, 1.920 mmol, 48.0% yield) as a brown solid: ¹H NMR (400 MHz,chloroform-d) δ 9.03 (s, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.84 (dd, J=1.8,1.1 Hz, 1H), 4.84 (s, 2H), 3.56 (s, 3H), 2.60 (s, 3H); Intermediate I-2Dwas contaminated with ca 10% of a side product5-bromo-2,7-dimethylquinoxaline.

Intermediate I-2

A mixture of Intermediate I-2E (900 mg, 3.37 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1369 mg,5.39 mmol), potassium acetate (661 mg, 6.74 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (110 mg, 0.135 mmol) in dioxane (15 mL) wasdegassed by bubbling argon for 10 min. The reaction vial was sealed andheated in microwave reactor at 130° C. for 30 min. The mixture wasdiluted with EtOAc/water, insoluble material was removed by filtration.The filtrate was extracted with EtOAc, washed with brine and dried oversodium sulfate, concentrated. The crude product was purified by flashchromatography (loading in chloroform, 0% to 20% dichloromethane in MeOHover 15 min using a 40 g silica gel cartridge). The desired fractionswere combined and concentrated and further purified by prep HPLC (methodA, 10-80% B in 8 mins; with a flow rate of 40 mL/min). The desiredfractions were placed in a SpeedVac overnight to remove solvent. Thematerial was dissolved in EtOAc, washed with diluted saturated sodiumbicarbonate (to remove TFA), brine, dried over sodium sulfate,concentrated and lyophilized to give Intermediate I-2 (360 mg, 1.550mmol, 46% yield) as a slightly colored solid. LC-MS: method A, RT=1.73min, MS (ESI) m/z: 233.1 boronic acid (M+H)⁺.

Intermediate I-3 2-bromo-6-methoxy-4-methylbenzo[d]thiazole

Intermediate I-3A: 6-methoxy-4-methylbenzo[d]thiazol-2-amine

To 4-methoxy-2-methylaniline (209 mg, 1.524 mmol) in acetonitrile (8 mL)was added ammonium thiocyanate (174 mg, 2.285 mmol). The mixture wasstirred at room temperature for 10 min. Then it was cooled with tapwater, and benzyltrimethylammonium tribromide (594 mg, 1.524 mmol) inacetonitrile (3.0 mL) was added dropwise. The mixture was then stirredat room temperature overnight. HPLC and LCMS indicated a clean reaction.The mixture was diluted with EtOAc/saturated sodium bicarbonate. Theorganic layer was collected, washed with brine, dried over sodiumsulfate. After evaporation of solvent, the crude product was dissolvedin a small amount of chloroform/MeOH, and charged to a 24 g silica gelcartridge which was eluted with 5% EtOAc in hexanes for 3 min., then a12 min gradient from 5% to 50% EtOAc in hexanes. The desired fractionswere combined and concentrated to give Intermediate I-3A (240 mg, 1.235mmol, 81% yield) as a pale solid. ¹H NMR (500 MHz, methanol-d₄) δ 7.03(d, J=2.5 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 3.79 (s, 3H), 2.46 (s, 3H);LC-MS: method A, RT=1.22 min, MS (ESI) m/z: 195.0 (M+H)⁺.

Intermediate I-3

t-Butyl nitrite (0.969 mL, 8.15 mmol) was added to copper(II) bromide(1820 mg, 8.15 mmol) in dry acetonitrile (20 mL) under argon. Themixture was stirred at room temperature for 10 min. A suspension ofIntermediate I-3A (931 mg, 4.79 mmol) in acetonitrile (30 mL) was addeddropwise. The reaction mixture was stirred at room temperature for 1.0h. LCMS indicated a clean reaction. Acetonitrile was removed undervacuum, the reaction mixture was diluted with EtOAc (30 mL) and 20 mL of0.5M HCl (aqueous). After separation, organic layer was washed with 0.5N HCl (20 mL×2), saturated sodium bicarbonate (15 mL), brine (15 mL) anddried over sodium sulfate. After evaporation of the solvent, the crudeproduct was purified by ISCO (80 g silica gel column, 20%EtOAc/hexanes). Removing solvent gave Intermediate I-3 as white solid(1.13 g, 91%). ¹H NMR (400 MHz, methanol-d₄) δ 7.29 (d, J=2.5 Hz, 1H),6.95-6.87 (m, 1H), 3.84 (s, 3H), 2.60 (s, 3H); LC-MS: (BEH C18 2.1×50mm; A: 10% MeCN-90% H₂O −0.1% TFA; B: 90% MeCN-10% H₂O −0.1% TFA;wavelength 220/254 nm; flow rate 5 mL/min; gradient time 2 min; 2 to 98%B) 1.11 min, [M+1]⁺=258.0, 260.0;

Intermediate I-42-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanamine

Intermediate I-4A: 2-chlorobenzo[d]thiazol-6-ol

Aluminum chloride (3.07 g, 22.99 mmol) was added to a solution of2-chloro-6-methoxybenzo[d]thiazole (1.53 g, 7.66 mmol) in toluene (50mL). The mixture was heated at 110° C. for 1.5 h. TLC indicated acomplete conversion of starting material. The reaction mixture wascooled to room temperature, quenched with ice-cold 1.0 N HCl (50 mL),stirred at room temperature for 30 min. The precipitate was collected byfiltration, washed with water (3×), saturated sodium bicarbonate (3×),water (3×) and air-dried for 1.0 h under vacuum. It was further driedunder high vacuum overnight to give Intermediate I-4A (1.18 g, 6.36mmol, 83% yield) as a pale brown solid. ¹H NMR (500 MHz, chloroform-d) δ7.82 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 7.03 (dd, J=8.8, 2.5 Hz,1H), 5.53 (s, 1H); LC-MS: method A, RT=1.62 min, MS (ESI) m/z: 186.0 and188.0 (M+H)⁺.

Intermediate I-4B:6-((tert-butyldimethylsilyl)oxy)-2-chlorobenzo[d]thiazole

To a stirred solution of Intermediate I-4A (1.15 g, 6.20 mmol) in DMF(20 mL) was added TBDMS-Cl (1.307 g, 8.67 mmol) and imidazole (0.738 g,10.84 mmol). After stirring at room temperature for 1.0 h, the reactionmixture was partitioned between EtOAc/water. The organic layer waswashed with brine and dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 24 g silica gel cartridge which was eluted with hexanesfor 3 min., then a 15 min gradient from 0% to 15% EtOAc in hexanes. Thedesired fractions were combined and concentrated to give IntermediateI-4B (1.78 g, 5.94 mmol, 96% yield) as a clear brownish oil. ¹H NMR (500MHz, chloroform-d) δ 7.81 (d, J=8.8 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H),7.01 (dd, J=8.8, 2.5 Hz, 1H), 1.04 (s, 9H), 0.26 (s, 6H); LC-MS: MethodA, 50 to 100% B. RT=2.34 min, MS (ESI) m/z: 300.0 and 302.0 (M+H)⁺.

Intermediate I-4C6-((tert-butyldimethylsilyl)oxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole

To Intermediate I-1 (1.45 g, 4.31 mmol), Intermediate I-4B (1.488 g,4.96 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.176 g, 0.216 mmol) was addedtoluene (9 mL) and EtOH (3 mL). The mixture was sonicated for 1 min, andflushed with argon. To this was added sodium carbonate, 2M (4.53 mL,9.06 mmol). The reaction mixture was heated in a microwave at 130° C.for 80 min. HPLC and LCMS indicated a clean reaction. To the reactionmixture was added EtOAc/water. The organic layers were collected, driedover sodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of toluene/chloroform and charged to a 80 gsilica gel cartridge which was eluted with 5% dichloromethane in hexanesfor 3 min., then a 18 min gradient from 5% to 75% dichloromethane inhexanes (flow rate 50 mL/min). The desired fractions were combined andconcentrated to give Intermediate I-4C (1.65 g, 3.48 mmol, 81% yield) asa bright yellow solid. ¹H NMR (500 MHz, chloroform-d) δ 8.76 (d, J=1.9Hz, 1H), 8.71 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.80 (dd, J=1.8, 1.0 Hz,1H), 7.68 (t, J_(HF)=71.80 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.07 (dd,J=8.7, 2.3 Hz, 1H), 2.70 (s, 3H), 1.07-1.05 (m, 9H), 0.30-0.28 (m, 6H);¹⁹F NMR (471 MHz, chloroform-d) δ −89.74 (s, 2F); LC-MS: method A,RT=2.89 min, MS (ESI) m/z: 474.1 (M+H)⁺.

Intermediate I-4D:2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol

To a solution of Intermediate I-4C (1.65 g, 3.48 mmol) in THF (15 mL) atroom temperature was added acetic acid (0.439 mL, 7.66 mmol), followedby addition of 1.0 N TBAF in THF (4.53 mL, 4.53 mmol) dropwise. Themixture was stirred at room temperature for 40 min. HPLC and LCMSindicated a completion of reaction. The mixture was diluted with EtOAc,washed with water, saturated sodium bicarbonate (2×), brine, and driedover sodium sulfate. After evaporation of the solvent, the crude productwas triturated with EtOAc/hexanes (1:4). The precipitate was collectedby filtration to give Intermediate I-4D (1.13 g) of the desired product.¹H NMR (500 MHz, chloroform-d) δ 8.58 (d, J=1.9 Hz, 1H), 8.53 (s, 1H),7.76 (d, J=8.8 Hz, 1H), 7.63 (s, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.50 (t,J_(HF)=71.80 Hz, 1H), 6.98 (s, 1H), 6.88 (dd, J=8.8, 2.5 Hz, 1H), 2.52(s, 3H); ¹⁹F NMR (471 MHz, chloroform-d) δ −89.75 (s, 2F); LC-MS: methodA, RT=2.24 min, MS (ESI) m/z: 360.0 (M+H)⁺.

Intermediate I-4E: tert-butyl(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate

A solution of tert-butyl (2-hydroxyethyl)carbamate (1.252 g, 7.76 mmol)and DIAD (1.510 mL, 7.76 mmol) in THF (6 mL) was added to a mixture ofIntermediate I-4D (0.93 g, 2.59 mmol) and triphenylphosphine (1.358 g,5.18 mmol) in THF (10 mL) heated at 70° C. dropwise with a syringe pumpin 3 h. At the end of addition, HPLC and LCMS indicated a completeconversion of starting material to the product. The mixture was dilutedwith EtOAc, washed with saturated sodium bicarbonate (2×), brine. Theorganic layers were collected, dried over sodium sulfate. Afterevaporation of solvent, the crude product was dissolved in a smallamount of chloroform and charged to a 80 g silica gel cartridge whichwas eluted with dichloromethane for 5 min., then a 18 min gradient from0% to 25% EtOAc in dichloromethane, flow rate 60 mL/min. The desiredfractions were combined and purified with a second ISCO (80 g) column,to give Intermediate I-4E (1.0 g, 1.990 mmol, 77% yield) as a yellowsolid. ¹H NMR (500 MHz, chloroform-d) δ 8.80 (d, J=1.7 Hz, 1H), 8.71 (s,1H), 8.06 (d, J=8.8 Hz, 1H), 7.81 (dd, J=1.8, 1.0 Hz, 1H), 7.68 (t,J_(HF)=71.68 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 7.15 (dd, 2.5 Hz, 1H),4.19-4.12 (m, 2H), 3.63 (d, J=5.0 Hz, 2H), 2.71 (s, 3H), 1.53-1.48 (s,9H); ¹⁹F NMR (471 MHz, chloroform-d) δ −89.75 (s, 2F); LC-MS: Method A,50 to 100% B. RT=2.20 min, MS (ESI) m/z: 503.0 (M+H)⁺.

Intermediate I-4

Intermediate I-4E (1.2 g, 2.388 mmol) was added 4.0 N HCl in dioxane(41.8 ml, 167 mmol), followed by addition of EtOAc (10 mL) to rinse thesolid residue on the flask wall. The mixture was left stirring at roomtemperature overnight. HPLC and LCMS indicated a clean reaction. Solventwas removed, chased twice with EtOAc, once with MeOH, and then driedunder high vacuum over the weekend to give Intermediate I-4 (1.0 g,2.279 mmol, 95% yield) as a bright yellow solid. ¹H NMR (500 MHz,methanol-d₄) δ 8.75 (d, J=1.7 Hz, 1H), 8.73 (s, 1H), 8.11 (d, J=8.8 Hz,1H), 7.91-7.89 (m, 1H), 7.69 (t, J_(HF)=71.53 Hz, 1H), 7.63 (d, J=2.5Hz, 1H), 7.29 (dd, J=8.9, 2.3 Hz, 1H), 4.38 (t, J=5.0 Hz, 2H), 3.42 (t,J=4.5 Hz, 2H), 2.71 (s, 3H); LC-MS: method A, RT=1.90 min, MS (ESI) m/z:403.0 (M+H)⁺.

Intermediate I-5N-(2-((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Intermediate I-5A: tert-butyl(2-(3-methyl-4-nitrophenoxy)ethyl)carbamate

In a round bottom flask, tert-butyl (2-hydroxyethyl)carbamate (3.0 g,18.61 mmol) was dissolved in DMF (20 mL) and mixed with4-fluoro-2-methyl-1-nitrobenzene (2.89 g, 18.61 mmol). K₂CO₃ (7.72 g,55.8 mmol) was added. Then the mixture was stirred at 100° C. overnight.On the next day, the reaction mixture was poured into ice water (50 mL)and was extracted with EtOAc (50 mL×2). The combined organic phases werewashed with brine, dried over Na₂SO₄, filtered, and concentrated to givea crude product that was purified by flash chromatography (80 g silicagel column, eluted with 0-100% EtOAc/Hexane gradient). Collectingdesired fractions and removing solvent gave the desired product as ayellow oil. (2.44 g, 8.2 mmol, 44.2%). ¹H NMR (400 MHz, chloroform-d): δ8.19-7.94 (m, 1H), 6.91-6.70 (m, 2H), 4.95 (br s, 1H), 4.14-4.05 (m,2H), 3.56 (q, J=5.3 Hz, 2H), 2.64 (s, 3H), 1.46 (s, 9H); LC-MS: methodH, RT=1.13 min, MS (ESI) m/z: 241.1 ([M+H—(CH₃)₃C]⁺).

Intermediate I-5B: tert-butyl(2-(4-amino-3-methylphenoxy)ethyl)carbamate

Intermediate I-5A (3.94 g, 13.30 mmol) was dissolved in MeOH (50 mL) andmixed with wet Pd—C (0.708 g, 0.665 mmol). After applying vacuum andrefilling with H2 3×, the mixture was treated with 1 atm H₂ for 4 h. Theresulting mixture was filtered over celite and washed with a smallamount of MeOH several times. Solvent was removed in vacuo to giveIntermediate I-5B as yellow oil. (3.28 g, 93%). ¹H NMR (500 MHz,CHLOROFORM-d) δ 6.67 (s, 1H), 6.62 (d, J=1.7 Hz, 2H), 5.00 (br. s., 1H),3.95 (t, J=5.1 Hz, 2H), 3.49 (d, J=5.0 Hz, 2H), 3.37 (br. s., 2H), 2.16(d, J=0.6 Hz, 3H), 1.46 (s, 9H); LC-MS: method H, RT=0.79 min, MS (ESI)m/z: 267.3).

Intermediate I-5C: tert-butyl(2-((2-amino-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) carbamate

To Intermediate I-5B (3.28 g, 12.3 mmol) in acetonitrile (30 mL) wasadded ammonium thiocyanate (1.406 g, 18.5 mmol). The mixture was stirredat room temperature for 10 min, cooled in an ice water bath, andbenzyltrimethylammonium tribromide (4.80 g, 12.3 mmol) in acetonitrile(20 mL) was added dropwise. The mixture was stirred at room temperaturefor 2 h, and then diluted with EtOAc/saturated sodium bicarbonate (100mL/30 mL). The layers were separated, and the aqueous phase wasextracted with EtOAc (30 mL×2). Then organic phases were combined,washed with saturated NaHCO₃(aqueous, 30 mL) and brine (30 mL), driedover Na₂SO₄, filtered, and concentrated on a rotary evaporator to giveIntermediate I-5C (3.972 g, 12.3 mmol, 100%) as a brown solid. The crudeproduct was used in the next step without further purification. ¹H NMR(400 MHz, chloroform-d): δ 6.97 (d, J=2.4 Hz, 1H), 6.75 (s, 1H), 5.13(br s, 2H), 5.00 (br s, 1H), 4.02 (t, J=5.1 Hz, 2H), 3.53 (d, J=4.8 Hz,2H), 2.53 (d, J=0.4 Hz, 3H), 1.46 (s, 9H); LC-MS: method H, RT=1.04 min,MS (ESI) m/z: 324.2.

Intermediate I-5D: tert-butyl(2((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl) carbamate

In a round bottom flask charged with a stirring bar, copper (II) bromide(441 mg, 1.976 mmol), and dry acetonitrile (5 mL) under argon,tert-butyl nitrite (204 mg, 1.976 mmol) was added. The mixture wasstirred at room temperature for 10 min. A suspension of IntermediateI-5C (376 mg, 1.163 mmol) in dry acetonitrile (5 mL) was added dropwise.The reaction mixture was stirred at room temperature for 1.0 h, and theacetonitrile was removed under vacuum. The reaction mixture was dilutedwith EtOAc (50 mL) and 40 mL of 0.5M HCl (aqueous). After separation,the organic layer was washed with 0.5 N HCl (aqueous, 30 mL×2),saturated sodium bicarbonate (aqueous, 30 mL), brine (20 mL), dried oversodium sulfate, filtered, and concentrated on a rotary evaporator. Theresidue was purified by flash chromatography (40 g silica gel column,0-50% EtOAc/hexane) to give the desired product as a colorless oil (340mg, 1.50 mmol, 76%). ¹H NMR (400 MHz, chloroform-d) δ 7.08 (d, J=2.2 Hz,1H), 6.88 (d, J=1.5 Hz, 1H), 4.98 (br s, 1H), 4.06 (t, J=5.1 Hz, 2H),3.56 (d, J=5.1 Hz, 2H), 2.67 (s, 3H), 1.46 (s, 9H); LC-MS: method H,RT=1.37 min, MS (ESI) m/z: 387.0, 389.0.

Intermediate I-5E: tert2((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)ethanamine

In a round bottom flask charged with a stirring bar, Intermediate I-5D(940 mg, 2.43 mmol) was dissolved in DCM (4 mL) and treated with TFA (2ml, 26.0 mmol) at room temperature for 1 hour. Solvent and extra TFAwere removed on a rotary evaporator and the residue was dissolved in 30mL of DCM and was washed with 20 mL of saturated NaHCO₃, 20 mL of brine,and dried over Na₂SO₄. Removing solvent gave the crude product usedwithout purification in the next step. (657 mg, 2.28 mmol, 94%) LC-MS:method H, RT=0.85 min, MS (ESI) m/z: 87.0, 289.0.

Intermediate I-5

Intermediate I-5E (534 mg, 1.86 mmol) was dissolved in a mixture of THF(5 mL) and DIEA (1.30 mL, 7.45 mmol). 4-Fluorobenzene-1-sulfonylchloride (362 mg, 1.862 mmol) in THF (5 mL) was added dropwise, and themixture was stirred at room temperature for 30 minutes. Solvent wasremoved on a rotary evaporator and the residue was purified by flashchromatography (40 g silica gel column, 0-100% EtOAc/hexane gradient) togive the title compound as a white solid (666 mg, 1.49 mmol, 80%). ¹HNMR (400 MHz, chloroform-d) δ 7.96-7.87 (m, 2H), 7.23-7.14 (m, 2H), 6.99(d, J=2.2 Hz, 1H), 6.79-6.76 (m, 1H), 4.05 (t, J=5.1 Hz, 2H), 3.46-3.36(m, 2H), 2.66 (s, 3H); LC-MS: method H, RT=1.37 min, MS (ESI) m/z: 444.9and 446.9.

Intermediate I-9 (2-methoxy-7-methylquinoxalin-5-yl)boronic acid

Intermediate I-9A: 5-bromo-2-methoxy-7-methylquinoxaline

To Intermediate I-1G (3.13 g, 10.83 mmol) dissolved in THF (20 mL) andMeOH (15 mL) at room temperature was added 4.3 M sodium methoxide inMeOH (7.55 mL, 32.5 mmol). The reaction mixture was stirred at roomtemperature overnight. Methanol was removed under vacuum. The reactionmixture was diluted with EtOAc, quenched with 0.5 N HCl (30.0 mL). Theorganic layer was washed with saturated sodium bicarbonate, brine, driedand concentrated to give Intermediate I-9A (2.7 g, 10.67 mmol, 99%yield) as a slightly yellow solid. ¹H NMR (500 MHz, chloroform-d) δ 8.48(s, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.60 (dd, J=1.8, 1.0 Hz, 1H), 4.10 (s,3H), 2.53 (s, 3H); LC-MS: Method A, 30 to 100% B. RT=1.71 min, MS (ESI)m/z: 253.0 and 255.0 (M+H)⁺.

Intermediate I-9

A mixture of Intermediate I-9A (700 mg, 2.77 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1053 mg,4.15 mmol), potassium acetate (679 mg, 6.91 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (113 mg, 0.138 mmol) in dioxane (14 mL) wasdegassed by bubbling argon for 5 min. It was then heated at 130° C. for40 min. The reaction mixture was mixed with EtOAc/water and stirred atroom temperature for 15 min. The insoluble material was removed byfiltration through a pad of wet celite. The organic layer was washedwith brine, dried over sodium sulfate and concentrated. The crudeproduct was purified by flash chromatography (loading in chloroform, 5%to 100% EtOAc in hexane over 15 min using a 80 g silica gel cartridge).The desired fractions were combined, concentrated and lyophilized toyield to yield Intermediate I-9 (362 mg, 1.659 mmol, 60 yield) as asolid. ¹H NMR (500 MHz, methanol-d₄) δ 8.41 (s, 1H), 7.69 (br. s., 1H),7.49 (br. s., 1H), 4.10 (s, 3H), 2.56 (s, 3H). LC-MS: method H, RT=0.83min, MS (ESI) m/z: 219.1 (M+H)⁺.

Intermediate I-12 2-methoxy-7-methylquinoxaline-5-carbothioamide

Intermediate I-12A: 2-methoxy-7-methylquinoxaline-5-carbonitrile

Intermediate I-9A (0.458 g, 1.810 mmol) and copper(I) cyanide (0.600 g,6.70 mmol) were dissolved in DMF (18.10 mL) and heated to reflux for 20hours. The reaction mixture was cooled to ambient temperature. Thereaction mixture was diluted with saturated NaHCO₃ and extracted withEtOAc. The organic layer was further washed with water then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 12 g silica gel column, 17minute gradient from 0 to 100% EtOAc in hexanes) to give IntermediateI-12A (247 mg, 1.24 mmol, 68.5%) as a white solid: ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.55 (s, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.78 (s, 1H), 4.11(s, 3H), 2.58 (s, 3H); LC-MS: Method H, RT=0.92 min, MS (ESI) m/z: 200.1(M+H)⁺.

Intermediate I-12

Intermediate I-12A (0.247 g, 1.240 mmol), sodium hydrosulfide (1.043 g,18.60 mmol), and magnesium chloride (1.771 g, 18.60 mmol) were dissolvedin DMF (12.40 mL) and stirred for 18 hours. The reaction mixture wasdiluted with water, which formed copious amounts of precipitates. Thereaction mixture was extracted thrice with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The solid was sonicated with DCM then filtered.The resulting solution was concentrated in vacuo to give IntermediateI-12 (111 mg, 0.476 mmol, 38.4%) as an orange solid: ¹H NMR (400 MHz,CHLOROFORM-d) δ 11.86 (br. s., 1H), 9.04 (d, J=2.0 Hz, 1H), 8.40 (s,1H), 8.32 (br. s., 1H), 7.82 (dd, J=1.9, 0.9 Hz, 1H), 4.11 (s, 3H), 2.61(s, 3H); LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 234.0 (M+H)⁺.

Intermediate I-14 5-iodo-7-methylquinoxalin-2(1H)-one

Intermediate I-14A: 2-iodo-4-methyl-6-nitroaniline

Iodine (4.59 g, 18.07 mmol) was dissolved in EtOH (65.7 mL). Next,4-methyl-2-nitroaniline (2.5 g, 16.43 mmol) and then silver sulfate(5.64 g, 18.07 mmol) were added and the reaction mixture was allowed tostir for 18 hours. The reaction mixture was diluted with EtOAc, filteredthrough a sintered glass funnel, and concentrated in vacuo. The crudematerial was redissolved in EtOAc and washed with saturated Na₂S₂O₃,saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to give Intermediate I-14A (4.65 g, 16.72 mmol, 100%) as anorange solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.97 (d, J=1.0 Hz, 1H),7.78 (d, J=2.0 Hz, 1H), 6.49 (br. s., 2H), 2.26 (s, 3H); LC-MS: MethodH, RT=0.98 min, MS (ESI) m/z: 279.0 (M+H)⁺.

Intermediate I-14B: bis-tert-butyl (2-iodo-4-methyl-6-nitroaniline)biscarbamate

Intermediate I-14A (4.65 g, 16.72 mmol), DMAP (0.204 g, 1.672 mmol), andBoc₂O (9.71 mL, 41.8 mmol) were dissolved in THF (27.9 mL) and stirredfor 18 hours. The reaction mixture was diluted with water and extractedwith EtOAc. The organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 220 g silica gel column, 50 minute gradientfrom 0 to 100% EtOAc in hexanes), to give Intermediate I-14B (5.4 g,11.29 mmol, 67.5%) as a light yellow solid: ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.94 (s, 1H), 7.78 (s, 1H), 2.43 (s, 3H), 1.40 (s, 18H);LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: (bis-deboc mass observed)278.9 (M+H)⁺.

Intermediate I-14C: methyl2-((tert-butoxycarbonyl)(2-iodo-4-methyl-6-nitrophenyl)amino)acetate

Intermediate I-14B (5.4 g, 11.29 mmol) was dissolved in DCM (18.82 mL)and TFA (1.740 mL, 22.58 mmol) and stirred for 30 minutes. The reactionmixture was diluted with DCM, quenched with saturated NaHCO₃, washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude material was dissolved in DMF (18.82 mL). Cs₂CO₃ (9.20 g, 28.2mmol) was added and stirred for 15 minutes. The reaction mixture turneddeep red. Methyl bromoacetate (1.249 mL, 13.55 mmol) was added and thereaction mixture was allowed to stir 24 hours. The reaction mixtureturned from deep red to yellow. The reaction mixture was diluted withEtOAc, washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 220 g silica gel column, 50 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate I-14C (3.51 g, 7.80 mmol,69.1%) as an orange solid: LC-MS: Method H, RT=1.00 min, MS (ESI) m/z:(deboc mass observed) 350.9 (M+H)⁺.

Intermediate I-14D: methyl2-((2-iodo-4-methyl-6-nitrophenyl)amino)acetate

Intermediate I-14C (3.51 g, 7.80 mmol) was dissolved in HCl in dioxane(4 M, 9.75 mL, 39.0 mmol) and stirred for 1 hour. The reaction mixturewas concentrated in vacuo to give Intermediate I-14D, which was useddirectly in the subsequent step without purification: LC-MS: Method H,RT=0.79 min, MS (ESI) m/z: 350.9 (M+H)⁺.

Intermediate I-14E: 5-iodo-7-methyl-3,4-dihydroquinoxalin-2(1H)-one

Intermediate I-14D (2.73 g, 7.80 mmol) was dissolved in MeOH (28.4 mL).HCl (2.60 mL, 31.2 mmol) then tin(II) chloride dihydrate (7.04 g, 31.2mmol) were added and the reaction mixture was heated to 65° C. for 3.5hours. The reaction mixture was cooled to ambient temperature,neutralized with 10 N NaOH and diluted with brine then EtOAc. Vigorousstirring was allowed for 15 minutes. The mixture was filtered throughcelite and concentrated in vacuo to give Intermediate I-14E (1.77 g,6.14 mmol, 79.0%) as an orange solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ7.57 (br. s., 1H), 7.17 (s, 1H), 6.48 (s, 1H), 4.17 (br. s., 1H), 4.02(d, J=1.8 Hz, 2H), 2.21 (s, 3H); LC-MS: Method H, RT=0.82 min, MS (ESI)m/z: 289.0 (M+H)⁺.

Intermediate I-14

Intermediate I-14E (1.7696 g, 6.14 mmol) was suspended in MeOH (17.86mL). 1 N NaOH (18.43 mL, 18.43 mmol) then H₂O₂ (30%)(3.23 mL, 36.9 mmol)were added and the reaction mixture stirred 24 hours. More H₂O₂ (3.23mL, 36.9 mmol) was added and the reaction mixture was stirred for 24hours. More H₂O₂ (3.23 mL, 36.9 mmol) was added and the reaction mixturewas stirred for 24 hours. The reaction mixture was diluted with ca 50 mLof water then about 50 mL of brine. The mixture was evaporated under anitrogen stream to remove MeOH. The aqueous material was extractedthrice with EtOAc. During the extractions, an off-white solidprecipitated. This precipitate was collected by suction filtration as togive Intermediate I-14 (1.35 g, 4.72 mmol, 77.0%): ¹H NMR (400 MHz,DMSO-d₆) δ 12.44 (br. s., 1H), 8.11 (s, 1H), 7.72 (d, J=1.5 Hz, 1H),7.09 (s, 1H), 2.37 (s, 3H); LC-MS: Method H, RT=0.80 min, MS (ESI) m/z:287.0 (M+H)⁺.

Intermediate I-15 (2-(ethoxycarbonyl)-7-methylquinoxalin-5-yl)boronicacid

Intermediate I-15A: 3-bromo-5-methylbenzene-1,2-diamine

2-bromo-4-methyl-6-nitroaniline (5.00 g, 21.64 mmol) was dissolved inMeOH (148 mL) and THF (18.50 mL). Ammonium chloride (23.15 g, 433 mmol)then zinc (14.15 g, 216 mmol) were added and the reaction mixture washeated to 40° C. for 1 h. The reaction mixture was cooled to ambienttemperature, concentrated in vacuo, re-dissolved in EtOAc and saturatedNa₂CO₃, and stirred vigorously for 10 minutes. The mixture was filteredthrough a sintered glass funnel and washed with more EtOAc. The organiclayer was further washed twice with water, washed with brine, dried withsodium sulfate, filtered, and concentrated in vacuo to yieldIntermediate I-15A (4.35 g, 21.63 mmol, 100% yield). ¹H NMR (400 MHz,CHLOROFORM-d) δ 6.81 (s, 1H), 6.48 (s, 1H), 3.66 (br. s., 2H), 3.46 (br.s., 2H), 2.19 (s, 3H). LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 201.0(M+H)⁺.

Intermediate I-15B: ethyl 5-bromo-7-methylquinoxaline-2-carboxylate

Intermediate I-15A (4.35 g, 21.63 mmol) and ethyl3-bromo-2-oxopropanoate (3.63 mL, 26.0 mmol) were dissolved in NMP (72.1mL) and allowed to stir at room temperature for 18 h open to air. Thereaction mixture was diluted with water and EtOAc. The layers wereseparated and the aqueous layer was back extracted with EtOAc (×3). Thecombined organic layer was washed with brine, dried with sodium sulfate,and concentrated under reduced pressure. The reaction mixture waspurified by ISCO column using 0-40% EtOAc in hexanes on a 220 g columnto yield a mixture of regioisomers. The reaction mixture was purified bySFC on a Chiralcel OD-H, 30×250 mm, 5 micron column using 20% IPA/80%CO₂ with 85 mL/min, 100 Bar, 40° C. to yield Intermediate I-15B (0.936g, 3.17 mmol, 14.66% yield) as a yellow solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 9.48 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 4.53 (q, J=7.0Hz, 2H), 2.55 (s, 3H), 1.44 (t, J=7.2 Hz, 3H). LC-MS: method H, RT=1.15min, MS (ESI) m/z: 295.1 (M+H)⁺.

Intermediate I-15

A mixture of Intermediate I-15B (0.100 g, 0.339 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.129 g,0.508 mmol), potassium acetate (0.083 g, 0.847 mmol) in dioxane (3.39mL) were degassed by bubbling argon for 5 min. PdCl₂(dppf)-CH₂Cl adduct(0.014 g, 0.017 mmol) was added and the mixture was sealed and heated inmicrowave at 130° C. for 30 min. The reaction mixture was diluted withwater and EtOAc. The layers were separated and the organic layer waswashed with brine, dried with sodium sulfate, and concentrated underreduced pressure to yield a brown oil. The reaction mixture was purifiedon Prep HPLC using Method A to yield Intermediate I-15 (0.027 g, 0.104mmol, 30.6% yield) as an off white solid. LC-MS: method H, RT=1.15 min,MS (ESI) m/z: 261.2 (M+H)⁺.

Intermediate I-16 (2-bromo-5-methoxy-7-methylthiazolo[5,4-b]pyridine

Intermediate I-16A: 1-(6-methoxy-4-methylpyridin-3-yl)thiourea

To a solution of 6-methoxy-4-methylpyridin-3-amine (0.150 g, 1.086 mmol)in acetone (1 mL) was added dropwise benzoyl isothiocyanate (0.161 mL,1.194 mmol). The reaction mixture was allowed to stir at roomtemperature for 2.5h. The reaction mixture was concentrated underreduced pressure and re-dissolved in tetrahydrofuran (1 mL). To thissolution was added sodium methoxide (0.5 M in MeOH) (3.26 mL, 1.628mmol), and the reaction mixture was allowed to stir at room temperaturefor 30 min. The reaction mixture was diluted with water and EtOAc. Thelayers were separated and the organic layer was washed with brine, driedwith sodium sulfate, and concentrated under reduced pressure. Thereaction mixture was triturated with Et₂O and filtered. The solid wascollected to yield Intermediate I-16A (0.148 g, 0.750 mmol, 69.1% yield)as a brown solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (s, 1H), 7.54(br. s., 1H), 6.69 (s, 1H), 6.51-5.18 (m, 2H), 3.93 (s, 3H), 2.28 (s,3H). LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 198.1 (M+H)⁺.

Intermediate I-16B: 5-methoxy-7-methylthiazolo[5,4-b]pyridin-2-amine

To a solution of Intermediate I-16A (0.146 g, 0.740 mmol) intetrahydrofuran (1 mL) was added benzyltrimethylammonium tribromide(0.289 g, 0.740 mmol). The reaction mixture was allowed to stir at roomtemperature for 2 hours. The reaction mixture was diluted with water andEtOAc. The layers were separated and the organic layer was washed withsaturated aqueous NaHCO₃, washed with brine, dried with sodium sulfate,and concentrated under reduced pressure. The reaction mixture waspurified on ISCO using 0-100% EtOAc in hexanes gradient on a 24 g columnto yield Intermediate I-16B (0.035 g, 0.179 mmol, 24.22% yield) as awhite solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.53 (d, J=0.7 Hz, 1H),5.00 (br. s., 2H), 3.91 (s, 3H), 2.49 (d, J=0.9 Hz, 3H). LC-MS: methodH, RT=0.93 min, MS (ESI) m/z: 196.1 (M+H)⁺.

Intermediate I-16

Copper (II) bromide (0.068 g, 0.305 mmol) and t-butyl nitrite (0.036 mL,0.305 mmol) were dissolved in MeCN (0.717 mL) and allowed to stir 10minutes. Intermediate I-16B (0.035 g, 0.179 mmol) was dissolved in MeCN(1.076 mL) and the copper solution was added. The reaction mixture wasallowed to stir at room temperature for 2 h. The reaction mixture wasdiluted with EtOAc, washed with 1 N HCl, saturated aqueous NaHCO₃,washed with brine, dried with sodium sulfate, filtered, and concentratedin vacuo to yield Intermediate I-16 (0.030 g, 0.116 mmol, 64.6% yield).¹H NMR (400 MHz, CHLOROFORM-d) δ 6.64 (d, J=1.1 Hz, 1H), 3.96 (s, 3H),2.62 (d, J=0.9 Hz, 3H). LC-MS: method H, RT=0.93 min, MS (ESI) m/z:359.1 (M+H)⁺.

Intermediate I-17 2-bromo-6-fluoro-5-methoxythiazolo[5,4-b]pyridine

Intermediate I-17A:N-((5-fluoro-6-methoxypyridin-3-yl)carbamothioyl)benzamide

To a solution of 5-fluoro-6-methoxypyridin-3-amine (0.100 g, 0.704 mmol)in acetone (1 mL) was added dropwise benzoyl isothiocyanate (0.104 mL,0.774 mmol). The reaction mixture was allowed to stir at roomtemperature for 3 h. The reaction mixture was diluted with water andEtOAc. The layers were separated and the organic layer was washed withbrine, dried with sodium sulfate, and concentrated under reducedpressure to yield Intermediate I-17A (0.215 g, 0.704 mmol, 100% yield):¹H NMR (400 MHz, CHLOROFORM-d) δ 12.48 (br. s., 1H), 9.12 (br. s., 1H),8.06 (d, J=2.0 Hz, 1H), 8.01 (dd, J=10.8, 2.2 Hz, 1H), 7.91 (d, J=1.1Hz, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.71-7.65 (m, 1H), 7.60-7.54 (m, 2H),4.06 (s, 3H). LC-MS: method H, RT=1.18 min, MS (ESI) m/z: 306.1 (M+H)⁺.

Intermediate I-17B: 1-(5-fluoro-6-methoxypyridin-3-yl)thiourea

To a solution of Intermediate I-17A (0.215 g, 0.704 mmol) intetrahydrofuran (1 mL) was added dropwise sodium methoxide (0.5 M inMeOH) (2.112 mL, 1.056 mmol). The reaction mixture was allowed to stirat room temperature for 18 h. The reaction mixture was diluted withwater and EtOAc. The layers were separated and the organic layer waswashed with brine, dried with sodium sulfate, and concentrated underreduced pressure. The residue was triturated with Et₂O, and the solidwas collected to yield Intermediate I-17B (0.09 g, 0.447 mmol, 63.5%yield) as a pale yellow solid. LC-MS: method H, RT=0.81 min, MS (ESI)m/z: 202.1 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.86 (d, J=2.2 Hz,1H), 7.63 (br. s., 2H), 7.32 (s, 1H), 4.03 (s, 3H).

Intermediate I-17C: 6-fluoro-5-methoxythiazolo[5,4-b]pyridin-2-amine

To a solution of Intermediate I-17B (0.078 g, 0.338 mmol) intetrahydrofuran (1 mL) was added benzyltrimethylammonium tribromide(0.151 g, 0.388 mmol). The reaction mixture was allowed to stir at roomtemperature for 2 hours. The reaction mixture was diluted with water andEtOAc. The layers were separated and the organic layer was washed withsaturated aqueous NaHCO₃, washed with brine, dried with sodium sulfate,and concentrated under reduced pressure. The reaction mixture waspurified on Prep HPLC using Method A to yield Intermediate I-17C (0.028g, 0.141 mmol, 36.3% yield) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.87 (br. s., 2H), 7.59 (d, J=9.7 Hz, 1H), 4.05 (s, 3H)LC-MS: method H, RT=0.84 min, MS (ESI) m/z: 200.1 (M+H)⁺.

Intermediate I-17

Copper (II) bromide (0.055 g, 0.247 mmol) and t-butyl nitrite (0.029 mL,0.247 mmol) were dissolved in MeCN (0.582 mL) and allowed to stir 10minutes. Intermediate I-17C (0.029 g, 0.146 mmol) was dissolved in MeCN(0.873 mL) and the copper solution was added. The reaction mixture wasdiluted with EtOAc, washed with 1 N HCl, saturated aqueous NaHCO₃, thenbrine, dried with sodium sulfate, filtered, and concentrated in vacuo toyield Intermediate I-17 (0.035 g, 0.133 mmol, 91% yield). ¹H NMR (400MHz, CHLOROFORM-d) δ 7.86 (d, J=9.9 Hz, 1H), 4.09 (s, 3H). LC-MS: methodH, RT=1.23 min, MS (ESI) m/z: 263.0 (M+H)⁺.

Intermediate I-20 2-bromo-6-methoxybenzo[d]thiazole-4-carbaldehyde

Intermediate I-20A: Methyl 2-amino-5-methoxybenzoate

2-amino-5-methoxybenzoic acid (250 mg, 1.496 mmol) was dissolved in MeOH(7478 μL). Thionyl chloride (327 μL, 4.49 mmol) was added and thereaction mixture was heated to reflux for 3 days. The reaction mixturewas concentrated in vacuo. The crude material was dissolved in EtOAc andwashed with 1 N NaOH, then water, then brine, dried (Na₂SO₄), filtered,and concentrated in vacuo to give Intermediate I-20A (190 mg, 1.049mmol, 70.1%) as a brown oil: ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.38 (d,J=3.1 Hz, 1H), 6.98 (dd, J=9.0, 3.1 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H),5.43 (br. s., 2H), 3.90 (s, 3H), 3.79 (s, 3H); LC-MS: Method H, RT=0.89min, MS (ESI) m/z: 182.1 (M+H)⁺.

Intermediate I-20B: Methyl2-amino-6-methoxybenzo[d]thiazole-4-carboxylate

Intermediate I-20A (190 mg, 1.049 mmol) was dissolved in MeCN (5243 μL).Ammonium thiocyanate (120 mg, 1.573 mmol) was added, followed bybenzyltrimethylammonium tribromide (409 mg, 1.049 mmol). After 4 hours,the reaction mixture was diluted with EtOAc, washed with saturatedNaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude material was purified by column chromatography (ISCO, 12 gsilica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes)to give Intermediate I-20B (100 mg, 0.42 mmol, 40%) as a brown solid: ¹HNMR (400 MHz, CHLOROFORM-d) δ 7.51 (d, J=2.6 Hz, 1H), 7.35 (d, J=2.6 Hz,1H), 5.89 (br. s., 2H), 3.99 (s, 3H), 3.88 (s, 3H); LC-MS: Method H,RT=0.82 min, MS (ESI) m/z: 239.1 (M+H)⁺.

Intermediate I-20C: Methyl2-bromo-6-methoxybenzo[d]thiazole-4-carboxylate

Copper(II) bromide (159 mg, 0.713 mmol) and t-butyl nitrite (85 μL,0.713 mmol) were dissolved in MeCN (1679 μL) and allowed to stir 10minutes. Intermediate I-20B (100 mg, 0.420 mmol) was dissolved in MeCN(2518 μL) and the copper solution was added. After 2 hours, the reactionmixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO₃,then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to giveIntermediate I-20C (100.6 mg, 0.333 mmol, 79%) as a red solid: ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.68 (d, J=2.6 Hz, 1H), 7.46 (d, J=2.6 Hz,1H), 4.05 (s, 3H), 3.93 (s, 3H); LC-MS: Method H, The compound did notionize.

Intermediate I-20D: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)methanol

Intermediate I-20C (93.5 mg, 0.309 mmol) was dissolved in toluene (2063μL) and THF (1032 μL) and cooled to −78° C. DIBAL-H (681 μL, 0.681 mmol)was added and the reaction mixture was warmed to ambient temperature for1 hour. The reaction was quenched with 1 N HCl (1 mL), diluted withEtOAc, filtered through celite, and concentrated in vacuo. The crudematerial was purified by column chromatography (ISCO, 12 g silica gelcolumn, 17 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate I-20D (28.1 mg, 0.103 mmol, 33%) as an off-white solid: ¹HNMR (400 MHz, CHLOROFORM-d) δ 7.17 (d, J=2.6 Hz, 1H), 7.04 (d, J=2.6 Hz,1H), 5.05 (d, J=6.6 Hz, 2H), 3.87 (s, 3H), 3.00 (t, J=6.5 Hz, 1H);LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 274/276 (M+H)⁺.

Intermediate I-20

Intermediate I-20D (188.8 mg, 0.689 mmol) was dissolved in CHCl₃ (4591μL). Manganese dioxide (359 mg, 4.13 mmol) was added and the reactionmixture was allowed to stir for 24 hours. More manganese dioxide (359mg, 4.13 mmol) was added and the reaction mixture was allowed to stirfor 3 days. The reaction mixture was filtered through celite andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate I-20 (136.3 mg, 0.501mmol, 72.7%) as a white solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ10.90-10.84 (m, 1H), 7.63-7.59 (m, 1H), 7.57-7.51 (m, 1H), 3.93 (s, 3H);LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 272/274 (M+H)⁺.

Intermediate I-22 4-bromo-6-methoxybenzo[d]thiazol-2-amine

2-Bromo-4-methoxyaniline (10 g, 49.5 mmol) was dissolved in MeCN (247mL). Ammonium thiocyanate (5.65 g, 74.2 mmol) was added, followed bybenzyltrimethylammonium tribromide (19.3 g, 49.5 mmol). After stirringfor 2 days, the reaction mixture was diluted with saturated NaHCO₃ andthe resulting solid was collected by suction filtration. The solid waswashed with water to give Intermediate I-22 (10.75 g, 41.5 mmol, 84%yield) as a light brown solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.19 (d,J=2.4 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 3.78 (s, 3H); LC-MS: Method H,RT=0.70 min, MS (ESI) m/z: 259/261 (M+H)⁺.

Intermediate I-252-(methoxymethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline, D₅

Intermediate I-25A: (5-bromo-7-methylquinoxalin-2-yl)methanol

NaBH₄ (135 mg, 3.56 mmol) and calcium chloride (197 mg, 1.779 mmol) weredissolved in THF (5270 μl). A solution of Intermediate I-15B (500 mg,1.779 mmol) in THF (1318 μl) was added dropwise, and the reactionmixture was allowed to stir at room temperature for 18 h. The reactionmixture was diluted with EtOAc, washed with water, washed with brine,dried with sodium sulfate, filtered, and concentrated under reducedpressure. The crude material was purified by column chromatography(ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAcin hexanes) to yield Intermediate I-25A (0.263 g, 1.04 mmol, 58%) as ayellow solid. ¹H NMR (500 MHz, CHLOROFORM-d) δ 8.85 (s, 1H), 7.92 (d,J=1.7 Hz, 1H), 7.79 (dd, J=1.7, 1.1 Hz, 1H), 5.04 (s, 2H), 3.73 (br. s.,1H), 2.58 (s, 3H). LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 253.1(M+H)⁺.

Intermediate I-25B: (5-bromo-7-methylquinoxalin-2-yl)methylmethanesulfonate

Intermediate I-25A (262.5 mg, 1.037 mmol) and TEA (0.434 mL, 3.11 mmol)were dissolved in DCM (20 mL) and methanesulfonic anhydride (217 mg,1.245 mmol) was added. The reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was diluted with DCM andwashed with saturated NaHCO₃, dried with sodium sulfate, filtered, andconcentrated in vacuo to yield Intermediate I-25B (0.343 g, 1.04 mmol,100%) as an orange solid. The material will be used crude in the nextstep. LC-MS: method H, RT=1.00 min, MS (ESI) m/z: 331.0 (M+H)⁺.

Intermediate I-25C: 5-bromo-2-(methoxymethyl)-7-methylquinoxaline, d₅

CD₃ONa was prepared by dissolving sodium metal (60 mg, 2.500 mmol) inCD₃OD (0.405 mL, 10 mmol) for 30 minutes. Intermediate I-25B (207 mg,0.625 mmol) was dissolved in THF (12 mL). CD₃ONa (71.3 mg, 1.250 mmol)was added, and the reaction mixture was allowed to stir at roomtemperature for 18 h. The reaction mixture was partially concentrated invacuo to remove THF, diluted with EtOAc and washed with water, washedwith brine, dried with sodium sulfate, filtered, and concentrated invacuo to yield Intermediate I-25C (0.118 g, 0.432 mmol, 69% yield). ¹HNMR (400 MHz, CHLOROFORM-d) δ 9.01 (s, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.82(dd, J=1.8, 0.9 Hz, 1H), 2.58 (s, 3H). LC-MS: method H, RT=0.90 min, MS(ESI) m/z: 272.1 (M+H)⁺.

Intermediate I-25

Intermediate I-25C (117.6 mg, 0.432 mmol), bis(pinacolato)diboron (165mg, 0.648 mmol), and potassium acetate (106 mg, 1.080 mmol) weredissolved in dioxane (4321 μl) and degassed for 5 minutes by bubblingwith argon. PdCl₂(dppf)-CH₂Cl₂ adduct (28.2 mg, 0.035 mmol) was addedand the reaction mixture was degassed for an additional 10 minutes. Thereaction mixture was heated to 130° C. in the microwave for 45 minutes.The reaction mixture was diluted with EtOAc and water and filtered. Thereaction mixture was further extracted twice with EtOAc. The combinedorganic layers were washed with brine, dried with sodium sulfate,filtered, and concentrated in vacuo to yield Intermediate I-25 (0.097 g,0.302 mmol, 70% yield). LC-MS: method H, RT=0.75 min, MS (ESI) m/z:238.2 (M+H)⁺. Observed the mass of the boronic acid in LC/MS.

Intermediate I-26 (R)-(2-chloro-4-methyl-7,8-dihydro-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]thiazol-7-yl)methyl acetate

Intermediate I-26A: (R)-5-methyl-2-(oxiran-2-ylmethoxy)benzaldehyde

To a solution of 2-hydroxy-5-methylbenzaldehyde (5 g, 36.7 mmol) in DMF(80 mL) was added (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (10.47g, 40.4 mmol) and Cs₂CO₃ (35.9 g, 110 mmol). The mixture was stirred atroom temperature overnight. LCMS indicated a completion of the reactionmixture. The mixture was diluted with EtOAc and water, extracted withEtOAc. The combined organic layer was washed with brine, dried overMgSO₄ and concentrated. The crude sample was purified with a 120 g ISCOcolumn eluted with 0-100% EtOAc/hexanes for 40 min. The desiredfractions were collected and concentrated to give Intermediate I-26A (7g, 36.4 mmol, 99% yield) as a colorless oil. ¹H NMR (400 MHz,chloroform-d) δ 10.50 (s, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.35 (ddd, J=8.6,2.4, 0.7 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 4.36 (dd, J=11.1, 3.0 Hz, 1H),4.05 (dd, J=11.1, 5.6 Hz, 1H), 3.40 (ddt, J=5.6, 4.1, 2.8 Hz, 1H), 2.94(dd, J=4.7, 4.1 Hz, 1H), 2.80 (dd, J=4.8, 2.6 Hz, 1H), 2.32 (s, 3H);LC-MS: method C, RT=1.59 min, MS (ESI) m/z: 193.0 (M+H)⁺.

Intermediate I-26B:(S)-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol

To a stirred solution of Intermediate I-26A (7 g, 36.4 mmol) indichloromethane (100 mL) cooled with an ice bath was added mCPBA (12.36g, 53.7 mmol). Next, trifluoroacetic acid (2.81 mL, 36.4 mmol) indichloromethane (10 mL) was added dropwise. Ice bath was removed and themixture was stirred at room temperature for 1.0 h. TLC and LCMSindicated no starting material remaining. The reaction mixture wasquenched by addition of saturated sodium bicarbonate, followed by 10%sodium thiosulfite (20.0 mL), extracted with dichloromethane. Theorganic layers were collected, washed with saturated sodium bicarbonate,brine and dried over sodium sulfate. After evaporation of solvent, thecrude product was dissolved in MeOH (100 mL), and K₂CO₃ (15.10 g, 109mmol) was added. The mixture was stirred overnight at room temperature.The reaction mixture was diluted with EtOAc and water, extracted withEtOAc, the combined organic layer was washed with brine, dried overMgSO₄ and concentrated. The crude sample was purified with a 120 g ISCOcolumn eluted with 0-100% EtOAc/hexanes for 40 min. The desiredfractions were combined and concentrated to give Intermediate I-26B(4.65 g, 25.8 mmol, 70.9% yield). ¹H NMR (400 MHz, chloroform-d) δ 6.78(d, J=8.1 Hz, 1H), 6.73 (d, J=1.3 Hz, 1H), 6.69-6.63 (m, 1H), 4.33-4.21(m, 2H), 4.15-4.05 (m, 1H), 3.96-3.76 (m, 2H), 2.26 (s, 3H). LC-MS:method C, RT=1.55 min, MS (ESI) m/z: 209.0 (M+H)⁺.

Intermediate I-26C:(R)-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl acetate

To a solution of Intermediate I-26B (4.6 g, 25.5 mmol) in THF (100 mL)at 0° C. was added TEA (8.89 mL, 63.8 mmol), followed by acetyl chloridein DCM (31.9 mL, 31.9 mmol) dropwise. The mixture was stirred at 0° C.for 10 min, and at room temperature for 1.0 h. The mixture was dilutedwith EtOAc, washed with water. The organic layer was washed with 0.5 NHCl, saturated sodium bicarbonate, brine and dried over sodium sulfate.After evaporation of solvent, Intermediate I-26C (5.3 g, 23.85 mmol, 93%yield) was obtained as a yellow oil. It was used for the next stepwithout further purification. ¹H NMR (400 MHz, chloroform-d) δ 6.76 (d,J=8.1 Hz, 1H), 6.72 (d, J=1.3 Hz, 1H), 6.68-6.61 (m, 1H), 4.40-4.33 (m,1H), 4.30 (dd, J=5.1, 4.4 Hz, 2H), 4.25 (dd, J=11.3, 2.3 Hz, 1H), 4.03(dd, J=11.4, 6.8 Hz, 1H), 2.25 (s, 3H), 2.11 (s, 3H). LC-MS: method C,RT=1.92 min, MS (ESI) m/z: 245.0 (M+H)⁺.

Intermediate I-26D:(R)-(7-methyl-6-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl acetate

To a solution of Intermediate I-26C (4.15 g, 18.67 mmol) in acetic acid(40 mL) cooled at 0° C. with an ice-bath was added fuming nitric acid(4.36 mL, 93 mmol) dropwise. The mixture was stirred at 0° C. for 1 h,then at room temperature for 30 min. TLC (PMA stain) indicated acompletion of the reaction. It was quenched with ice water. The aqueouswas removed and the organic layer was washed with saturated sodiumbicarbonate (3×), brine and dried over sodium sulfate. After evaporationof solvent, Intermediate I-26D (4.6 g, 17.21 mmol, 92% yield) wasobtained as an off-white solid which was used for the next step withoutfurther purification. ¹H NMR (400 MHz, chloroform-d) δ 7.71 (s, 1H),6.83 (s, 1H), 4.54-4.45 (m, 1H), 4.39-4.28 (m, 3H), 4.09 (dd, J=11.9,7.0 Hz, 1H), 2.55 (d, J=0.4 Hz, 3H), 2.13 (s, 3H). LC-MS: method C,RT=1.90 min, MS (ESI) m/z: 290.0 (M+H)⁺.

Intermediate I-26E:(R)-(6-amino-7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl acetate

To a solution of Intermediate I-26D (5.3 g, 19.83 mmol) in MeOH (80 mL)and THF (80 mL) cooled with an ice bath was added ammonium chloride(16.97 g, 317 mmol) and zinc dust (10.37 g, 159 mmol). The mixture wasstirred at 0° C. for 30 min, and at room temperature for 1.0 h. MeOH andTHF were removed under vacuum. The residue was diluted withEtOAc/saturated sodium bicarbonate and stirred at room temperature for 3min. The mixture was filtered through a pad of wet celite to removeinsoluble material. The filtrate was collected, organic layer was washedwith brine, dried over sodium sulfate, concentrated to give IntermediateI-26E (4.7 g, 19.81 mmol, 100% yield) as off-white solid. ¹H NMR (400MHz, chloroform-d) δ 6.63 (s, 1H), 6.25 (s, 1H), 4.38-4.20 (m, 4H),4.06-3.95 (m, 1H), 3.35 (br. s., 2H), 2.11 (s, 3H), 2.09 (s, 3H). LC-MS:method C, RT=1.14 min, MS (ESI) m/z: 238.0 (M+H)⁺.

Intermediate I-26F(R)-(2-amino-4-methyl-7,8-dihydro-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]thiazol-7-yl)methylacetate

To Intermediate I-26E (4.7 g, 19.81 mmol) dissolved in acetonitrile (120mL) was added ammonium thiocyanate (2.262 g, 29.7 mmol). The mixture wasstirred at room temperature for 10 min. Benzyltrimethylammoniumtribromide (8.11 g, 20.80 mmol) in acetonitrile (20 mL) was addeddropwise (5 min). The reaction mixture was stirred at room temperatureovernight, diluted with EtOAc/THF/saturated sodium bicarbonate. Theinsoluble material was removed by filtration. The organic layer of thefiltrate was collected, washed with brine, dried over sodium sulfate.After evaporation of solvent, Intermediate I-26F (5.8 g, 19.71 mmol, 99%yield) was obtained as a yellow solid. ¹H NMR (400 MHz, chloroform-d) δ6.73 (d, J=0.7 Hz, 1H), 5.10 (s, 2H), 4.47-4.28 (m, 4H), 4.14 (dd,J=11.3, 6.9 Hz, 1H), 2.45 (d, J=0.7 Hz, 3H), 2.12 (s, 3H). LC-MS: methodC, RT=1.46 min, MS (ESI) m/z: 295.0 (M+H)⁺.

Intermediate I-26

To a suspension of Intermediate I-26F (5.8 g, 19.71 mmol) in dryacetonitrile (80 mL) was added copper (II) chloride (4.5 g, 33.5 mmol),followed by tert-butyl nitrite (4.56 mL, 34.5 mmol) dropwise. Thereaction mixture was stirred at room temperature for 2 h. LCMS indicateda completion of the reaction. Acetonitrile was removed under vacuum, thereaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. Theorganic layer was collected, washed with 0.5 N HCl (2×), saturatedsodium bicarbonate, brine and dried over sodium sulfate. Afterevaporation of solvent, the crude product was purified with a 220 g ISCOcolumn eluted with 0% to 70% EtOAc in hexanes over 60 min. The desiredfraction was collected and concentrated to yield Intermediate I-26 (3.9g, 12.43 mmol, 63.1% yield) as an off-white solid. ¹H NMR (400 MHz,chloroform-d) δ 6.89 (d, J=0.7 Hz, 1H), 4.55-4.28 (m, 4H), 4.18 (dd,J=11.4, 7.0 Hz, 1H), 2.59 (s, 3H), 2.13 (s, 3H). LC-MS: method C,RT=2.18 min, MS (ESI) m/z: 314.0 (M+H)⁺.

Intermediate I-277-((tert-butyldimethylsilyloxy)methyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

Intermediate I-27A: 8-bromo-3-methoxyquinoxaline-6-carbaldehyde

To a solution of Intermediate I-9A (1 g, 3.95 mmol) in CCl₄ (20 mL) wasadded NBS (1.547 g, 8.69 mmol) and benzoic peroxide (0.115 g, 0.474mmol). The mixture was heated at reflux (95° C. oil bath) for 3 h. TLCand LCMS indicated a completion of the reaction. The mixture was cooledto room temperature and filtered. The filtrate was concentrated to ayellow solid. The crude sample was dissolved in THF (10 ml) and silvernitrate (6.71 g, 39.5 mmol) in water (10 ml) was added. The mixture wasstirred at 95° C. for 1 h. LCMS indicated a completion of the reaction.The mixture was cooled to room temperature and poured to 60 ml of water.The mixture was filtered and the filter cake was washed with CHCl₃ for 3times. The combined filtrate was extracted with CHCl₃ and the organiclayer was combined, washed with NaHCO₃ and brine dried over MgSO₄ andconcentrated to Intermediate I-27A (1 g, 3.74 mmol, 95% yield). Thecrude sample was used for next step without purification. LC-MS: methodC, RT=1.84 min, MS (ESI) m/z: 267 and 269 (M+H)⁺.

Intermediate I-27B: (8-bromo-3-methoxyquinoxalin-6-yl)methanol

Intermediate I-27A (1.055 g, 3.95 mmol) suspended in THF (10 mL) andMeOH (10 mL) was treated with NaBH₄ (0.149 g, 3.95 mmol) at roomtemperature for 15 min. The reaction mixture turned to a clear solution.LCMS indicated a completion of the reaction. Saturated NH₄Cl was addedto quench the reaction. After stirring at room temperature for 10 min,it was diluted with EtOAc and water. The organic layer was washed withbrine, dried over MgSO₄ and concentrated. The crude product was purifiedwith a 120 g ISCO column eluted with 0-100% EtOAc in hexanes. Thedesired fraction was collected and concentrated to give IntermediateI-27B (380 mg, 1.412 mmol, 35.7% yield). ¹H NMR (400 MHz, chloroform-d)δ 8.54 (s, 1H), 8.01-7.77 (m, 2H), 4.90 (s, 2H), 4.13 (s, 3H). LC-MS:method C, RT=1.64 min, MS (ESI) (m/z) 269 and 271 (M+H)⁺.

Intermediate I-27C5-bromo-7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxaline

To a stirred solution of Intermediate I-27B (380 mg, 1.412 mmol) in DMF(5 mL) was added TBDMS-Cl (319 mg, 2.118 mmol) and imidazole (173 mg,2.54 mmol). The reaction mixture was stirred at room temperature for 1.0h. TLC and LCMS indicated a clean reaction. The mixture was partitionedbetween EtOAc/water. The organic layer was washed with water, brine,dried over sodium sulfate. After evaporation of solvent, the crudeproduct was dissolved in a small amount of chloroform and charged to a40 g silica gel cartridge which was eluted with hexanes for 3 min., thena 20 min gradient from 0% to 15% EtOAc in hexanes. The desired fractionswere combined and concentrated to give Intermediate I-27C (480 mg, 1.252mmol, 89% yield) as a white solid. LC-MS: method C, RT=2.74 min, MS(ESI) (m/z) 383 and 385 (M+H)⁺.

Intermediate I-27

A mixture of Intermediate I-27C (100 mg, 0.261 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (99 mg,0.391 mmol), potassium acetate (64.0 mg, 0.652 mmol) in dioxane (2 mL)was degassed with argon for 5 min,then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (10.65 mg, 0.013 mmol) was added. The mixturewas sealed and heated in microwave reactor at 130° C. for 30 min. LCMSindicated a clean reaction. The mixture was diluted with EtOAc/water,insoluble material was removed by filtration. The filtrate was extractedwith EtOAc, washed with brine, dried over sodium sulfate. Afterevaporation of solvent, the crude product was dissolved in a smallamount of toluene and charged to a 40 g silica gel cartridge which waseluted with 5% EtOAc in hexanes for 2 min., then a 18 min gradient from5% to 75% EtOAc in hexanes. The desired fractions were combined,concentrated and lyophilized to give Intermediate I-27 (105 mg, 0.244mmol, 94% yield) as a pale solid. ¹H NMR (400 MHz, chloroform-d) δ 8.39(s, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.96 (dt, J=2.0, 1.0 Hz, 1H), 4.96 (s,2H), 4.13 (s, 3H), 1.45 (s, 12H), 1.00 (s, 9H), 0.16 (s, 6H). LC-MS:method C, RT=2.73 min, MS (ESI) (m/z) 349 (M+H)⁺ (boronic acid).

Intermediate I-287-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

Intermediate I-28A: 2-bromo-4-chloro-6-nitroaniline

A solution of 4-chloro-2-nitroaniline (10 g, 57.9 mmol) in acetic acid(50 mL) was cooled to 0° C. with an ice bath. Bromine (3.28 mL, 63.7mmol) was added dropwise, and the mixture was stirred at roomtemperature for 1 hr, and then poured into ice water. The precipitatedsolid was filtered and was washed with water several times. The filtercake was re-dissolved in EtOAc, dried over sodium sulfate, filtered andconcentrated in vacuo to give the title compound as a yellow solid(14.66 g, 100%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (d, J=2.4 Hz, 1H),8.02 (d, J=2.6 Hz, 1H), 7.27 (br s, 2H); LC-MS: method H, RT=1.15 min,MS (ESI) m/z: 250.9 and 252.9 (M+H)⁺.

Intermediate I-28B: tert-butylN-(2-bromo-4-chloro-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate

In a round bottom flask charged with a stirring bar, Intermediate I-28A(5 g, 19.88 mmol) was dissolved in THF (30 mL). DMAP (0.243 g, 1.988mmol) was added, followed by di-tert-butyl dicarbonate (11.54 mL, 49.7mmol). The reaction mixture was stirred at room temperature for 1 hour,and then solvent was removed on a rotary evaporator. The residue waspurified by flash chromatography (120 g silica gel column eluted with0-100% EtOAc/Hexane) to give the title compound as a white solid (8.2 g,18.1 mmol, 91%). ¹H NMR (400 MHz, chloroform-d): 7.97 (d, J=2.4 Hz, 1H),7.90 (d, J=2.4 Hz, 1H), 1.42 (s, 18H); LC-MS: method H, RT=1.04 min, MS(ESI) m/z: 250.9 and 252.9 (M+H-2Boc)⁺.

Intermediate I-28C: tert-butyl (2-bromo-4-chloro-6-nitrophenyl)carbamate

To a solution of Intermediate I-28B (8.2 g, 18.15 mmol) in DCM (50 mL)was added TFA (2.80 mL, 36.3 mmol) and the mixture was stirred at roomtemperature for 1 hour. Saturated NaHCO₃(aqueous 30 mL) was added to themixture. After stirring at room temperature for 10 minutes, the layerswere separated and the aqueous layer was extracted by DCM (30 mL×2). Thecombined organic solution was washed with brine, dried over Na₂SO₄ andconcentrated to give the title compound as a yellow solid (6.32 g, 18.0mmol, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (br s, 1H), 8.24 (d, J=2.4Hz, 1H), 8.12 (d, J=2.4 Hz, 1H), 1.43 (br s, 9H); LC-MS: method H,RT=0.82 min, MS (ESI) m/z: 250.9 and 252.9 (M+H-Boc)⁺.

Intermediate I-28D: methyl2-((2-bromo-4-methyl-6-nitrophenyl)amino)acetate

To a solution of Intermediate I-28C (6.32 g, 18.0 mmol) in DMF (30 mL)was added Cs₂CO₃ (14.64 g, 44.9 mmol. Methyl 2-bromoacetate (5.50 g,36.0 mmol) was added dropwise and the mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was diluted with 100 mLof EtOAc and 50 mL of water. After separation, the aqueous layer wasextracted by EtOAc (50 mL), and the combined organic layers were washedwith brine and concentrated. The residue was purified by flashchromatography (120 g silica gel column, eluted with 0-50% EtOAc/Hex) togive the title compound (7.55 g, 17.8 mmol, 99%) as a yellow oil. ¹H NMR(400 MHz, chloroform-d) δ 7.92-7.81 (m, 2H), 4.58 (d, J=17.6 Hz, 1H),3.99 (d, J=17.4 Hz, 1H), 3.69 (s, 3H), 1.38 (s, 9H); LC-MS: method H,RT=1.23 min, MS (ESI) m/z: 366.9 and 368.9 (M+H-56)⁺.

Intermediate I-28E: methyl2-((2-bromo-4-chloro-6-nitrophenyl)amino)acetate, TFA salt

Intermediate I-28D (5.6 g, 13.22 mmol) was dissolved in DCM (30 mL) andwas treated with TFA (10.18 mL, 132 mmol) at room temperature overnight.On the next day, the solvent was removed and the crude product was usedin the next step without purification. LC-MS: method H, RT=1.22 min, MS(ESI) m/z: 323.0 and 324.9 (M+H)⁺.

Intermediate I-28F: 5-bromo-7-chloro-3,4-dihydroquinoxalin-2(1H)-one

In a round bottom flask charged with a stirring bar, Intermediate I-28E(6.0 g, 18.55 mmol) was dissolved in MeOH (60 mL), and concentrated HCl(4.64 mL, 55.6 mmol) was added, followed by SnCl₂ (14.07 g, 74.2 mmol).The reaction mixture was stirred at 60° C. overnight. On the next day,after cooling to room temperature, another 2 equivalents of SnCl₂ wasadded to the reaction mixture. After 2 h at 60° C., the reaction mixturewas cooled to room temperature; the precipitate was filtered, washedwith small amount of MeOH, and dried to give a white solid as desiredproduct. The filtrate was concentrated on a rotary evaporator and thenpartitioned between 150 mL of EtOAc and 30 mL of water. Next, 4M NaOH(aqueous) was added to adjust the pH to 12. The solid was filtered on aCelite pad and the filter cake was washed with EtOAc. The layers wereseparated and the aqueous phase was extracted twice with EtOAc. Thecombined organic phases were washed with saturated NaHCO₃(aqueous),brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to giveadditional product. Combining material gave5-bromo-7-chloro-3,4-dihydroquinoxalin-2(1H)-one (3.55 g, 13.58 mmol,73.2% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s,1H), 7.12 (d, J=2.2 Hz, 1H), 6.85-6.66 (m, 1H), 5.83 (s, 1H), 3.82 (d,J=2.0 Hz, 2H); LC-MS: method H, RT=1.02 min, MS (ESI) m/z: 261.0 and263.0 (M+H)⁺.

Intermediate I-28G: 5-bromo-7-chloroquinoxalin-2-ol

In 1 L round bottom flask charged with a stirring bar, IntermediateI-28F (3.84 g, 14.7 mmol) was suspended in MeOH (50 mL), and H₂O₂ (15.00mL, 147 mmol, 30% in water) was added, followed by 4N NaOH (11.01 mL,44.1 mmol). The mixture was stirred at room temperature for 5 minutes,and then heated at 60° C. for 15 minutes. Heating was removed and thereaction mixture was stirred at room temperature over the weekend.Another 5 mL of H₂O₂ was added and the mixture was stirred at roomtemperature for 2 h. The reaction mixture was concentrated on a rotaryevaporator. The residual mixture was cooled in an ice bath, and 6 N HClwas added to adjust the pH value to 2-3, followed by 200 mL of EtOAc.After shaking and separation, the aqueous layer was extracted with EtOAc(50 mL×2). The combined organic phases were combined and dried overNa₂SO₄. Removing solvent in vacuo gave the title compound as a brownsolid. (2.51 g, 9.70 mmol, 66%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.63 (brs, 1H), 8.23 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H);LC-MS: method H, RT=1.01 min, MS (ESI) m/z: 258.9 and 260.9 (M+H)⁺.

Intermediate I-28H: 5-bromo-7-chloro-2-methoxyquinoxaline

In a round bottom flask charged with a stirring bar, Intermediate I-28G(1.60 g, 6.17 mmol) was suspended in POCl₃ (10 mL, 107 mmol), and themixture was refluxed for 2 h. Excess POCl₃ was removed on a rotaryevaporator and the residue was dried in vacuo for 30 minutes to give abrown solid. This brown solid was suspended in MeOH (30 mL), andanhydrous K₂CO₃ (1.704 g, 12.33 mmol) was added. The mixture was stirredat room temperature for 10 minutes, and then refluxed for 2 h. Aftercooling to room temperature, the solvent was removed on a rotaryevaporator. The residue was dissolved in 100 ml of EtOAc, washed withwater, brine, dried over Na₂SO₄, filtered, and concentrated to give thecrude product. The crude product was purified by flash chromatography(80 g silica gel column, 0-50% EtOAc/Hexane) to give Intermediate I-28H(1.02 g, 3.73 mmol, 60.5% yield) as a yellow solid. ¹H NMR (400 MHz,chloroform-d): δ 8.53 (s, 1H), 7.87-7.83 (m, 2H), 4.12 (s, 3H); LC-MS:method J, RT=0.96 min, MS (ESI) m/z: 273.0 and 275.0 (M+H)⁺.

Intermediate I-28

In a microwave vial charged with a stirring bar, Intermediate I-28H (330mg, 1.207 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (460 mg,1.810 mmol), potassium acetate (296 mg, 3.02 mmol) were mixed with1,4-dioxane (10 mL). After degassing with bubbling N₂ for 10 minutes,PdCl₂(dppf)-CH₂Cl₂ adduct (49.3 mg, 0.060 mmol) was added. The vial wassealed and was heated by microwave to 120° C. for 60 minutes. Aftercooling to room temperature, the reaction mixture was diluted by adding40 mL of EtOAc and 30 mL of water. After separation, the aqueous layerwas extracted with EtOAc (20 mL×2). The combined organic layers weredried over Na₂SO₄ and concentrated on a rotary evaporator. The residuewas purified by flash chromatography (40 g silica gel column, 0-100%EtOAc/hexane gradient in 10 minutes, 100% EtOAc for 10 minutes) to giveIntermediate I-28 as a yellow solid. (293 mg, 76%). ¹H NMR (400 MHz,chloroform-d): 8.53 (s, 1H), 7.92-7.85 (m, 2H), 4.08 (s, 3H), 1.45 (s,12H); LC-MS: method H, RT=1.09 min, MS (ESI) m/z: 239.1 (M+H-82)⁺.

Intermediate I-297-chloro-2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

Intermediate I-29A: tert-butyl(2-bromo-4-chloro-6-nitrophenyl)(3-methoxy-2-oxopropyl)carbamate

To Intermediate I-28C (2.0 g, 5.69 mmol) in DMF (20 mL) at 0° C. wasadded cesium carbonate (3.24 g, 9.96 mmol). The brown solution wasstirred at 0° C. for 10 min, followed by addition of Intermediate I-2B(1.140 g, 6.83 mmol) in DMF (5.0 mL). The brown solution turned yellow.The mixture was stirred at 0° C. for 15 min. The mixture was dilutedwith EtOAc, washed with water, brine, dried over sodium sulfate andconcentrated. The crude product was purified by flash chromatography (80g silica gel column, 0% to 60% EtOAc/hexane over 18 min) to yield thedesired product (2.01 g, 81%) as a yellow oil. ¹H NMR (400 MHz,chloroform-d): δ 7.95-7.80 (m, 2H), 4.65 (d, J=18.3 Hz, 1H), 4.22 (d,J=18.0 Hz, 1H), 4.09 (s, 2H), 3.42 (s, 3H), 1.37 (s, 9H); LC-MS: methodH, RT=1.20 min, MS (ESI) m/z: 383.0 (M+H-54)⁺.

Intermediate I-29B: 5-bromo-7-chloro-2-(methoxymethyl)quinoxaline

To Intermediate I-29A (2.0 g, 4.57 mmol) in ethyl acetate (10 mL) wasadded HCl in 1,4-dioxane (11.42 mL, 45.7 mmol) and the mixture wasstirred at room temperature for 20 min. LCMS indicated a clean reaction.Solvent was removed under vacuum, and chased with EtOAc once to give thedeprotected intermediate as yellow oil. The deprotected intermediate wasdissolved in THF (40 mL). Concentrated HCl (aqueous) (1.142 mL, 13.71mmol) was added, followed by SnCl₂ (3.47 g, 18.28 mmol). The mixture wasstirred in an oil bath at 40° C. for 4.0 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc (100 mL)/water(50 mL). The organic phase was neutralized with saturated sodiumbicarbonate, stirred at room temperature for 15 min, and the precipitatewas removed by filtration with a pad of wet Celite. The organic solutionwas washed with brine, dried over sodium sulfate and concentrated. Thecrude product was purified by flash chromatography (loading inchloroform, 0% to 40% EtOAc in hexane over 20 min using an 80 g silicagel cartridge) to yield a brown solid (0.48 g, 36.5%). ¹H NMR (400 MHz,chloroform-d) δ 9.07 (s, 1H), 8.06 (s, 2H), 4.83 (s, 2H), 3.56 (s, 3H);LC-MS: method J, RT=1.20 min, MS (ESI) m/z: 287.1, 289.0 (M+H)⁺.

Intermediate I-29

In a microwave vial charged with a stirring bar, Intermediate I-29B (475mg, 1.652 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (629 mg,2.478 mmol) and potassium acetate (405 mg, 4.13 mmol) were mixed in1,4-dioxane (10 mL). After degassing with bubbling N₂ for 10 minutes,Pd(dppf)₂Cl₂.CH₂Cl₂ (67.5 mg, 0.083 mmol) was added. The vial was sealedand was irradiated in the microwave at 120° C. for 60 minutes. Solventwas removed and the residue was purified by flash chromatography (24 gsilica gel column, 0-100% EtOAc/Hexane) to give Intermediate I-29 (432mg, 76%) as an off-white solid. ¹H NMR (400 MHz, chloroform-d) δ 9.07(s, 1H), 8.12 (d, J=2.4 Hz, 1H), 8.08 (d, J=2.2 Hz, 1H), 4.78 (s, 2H),3.51 (s, 3H), 1.24 (s, 12H); LC-MS: method J, RT=1.20 min, MS (ESI) m/z:253.0 (M+H-82)⁺.

Intermediate I-30 to Intermediate I-34

Intermediate I-30 to Intermediate I-34 were synthesized by following thegeneral procedures described in Intermediate I-28 and I-29.

LCMS LCMS [M + H]⁺ RT (Min)/ Intermediate Structure m/z Method NMR I-30

237.1* 1.00/H I-31

287.2* 0.61/J I-32

303.2* 0.73/J I-33

277.1* 0.92/J I-34

219.1* 0.86/H *(M + H)⁺ of boronic acid

Intermediate I-35 (7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)boronicacid

Intermediate I-35A: 4-bromo-2-chloro-6-nitroaniline

A mixture of 4-bromo-2-nitroaniline (10.82 g, 49.9 mmol) and NCS (8.32g, 62.3 mmol) in DMF (100 mL) was heated to 100° C. for 1 h. Aftercooling to room temperature, the solution was poured into ice water. Theyellow precipitate was collected by filtration and was washed withwater. The solid was dissolved in dichloromethane (100 mL) and theorganic phase was washed with water and brine, dried (Na₂SO₄), filtered,and concentrated to yield the title compound (11.54 g, 45.9 mmol, 92%yield) as a yellow solid. ¹H NMR (400 MHz, chloroform-d) δ 8.26 (d,J=2.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 6.57 (br s, 2H).

Intermediate I-35B: tert-butylN-(4-bromo-2-chloro-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate

Intermediate I-35B (11.75 g, 87%) was made as a yellow solid fromIntermediate I-35A (7.52 g, 29.9 mmol) via the same procedure asIntermediate I-28B. ¹H NMR (400 MHz, chloroform-d) δ 8.08 (d, J=2.2 Hz,1H), 7.89 (d, J=2.2 Hz, 1H), 1.42 (s, 18H).

Intermediate I-35C: tert-butyl (4-bromo-2-chloro-6-nitrophenyl)carbamate

Intermediate I-35C (5.2 g, 14.8 mmol, 98%) was made as a brown waxysolid from Intermediate I-35B (6.8 g, 15.0 mmol) via the same procedureas Intermediate I-28C. ¹H NMR (400 MHz, chloroform-d) δ 8.00 (d, J=2.2Hz, 1H), 7.81 (d, J=2.2 Hz, 1H), 6.92 (br s, 1H), 1.50 (s, 9H)

Intermediate I-35D: methyl2-((4-bromo-2-chloro-6-nitrophenyl)(tert-butoxycarbonyl)amino)acetate

Intermediate I-35D (5.4 g, 12.8 mmol, 87%) was made as a yellow oil fromIntermediate I-35C (5.2 g, 14.8 mmol) via the same procedure asIntermediate I-28D. ¹H NMR (400 MHz, chloroform-d) δ 7.99 (d, J=2.2 Hz,1H), 7.88-7.85 (m, 1H), 4.49 (d, J=17.4 Hz, 1H), 4.07 (d, J=17.4 Hz,1H), 3.71-3.67 (m, 3H), 1.37 (s, 9H); LC-MS: method H, RT=1.04 min, MS(ESI) m/z: 323.0 and 325.0 (M+H-100)⁺.

Intermediate I-35E: methyl2-((4-bromo-2-chloro-6-nitrophenyl)amino)acetate

Intermediate I-35E (4.15 g, 12.8 mmol, 100%) was made as a brown oilfrom Intermediate I-35D (5.44 g, 12.8 mmol) via the same procedure asIntermediate I-28E. LC-MS: method H, RT=1.0 min, MS (ESI) m/z: 323.1 and325.0 (M+H)⁺.

Intermediate I-35F: 7-bromo-5-chloro-3,4-dihydroquinoxalin-2(1H)-one

Intermediate I-35F (3.02 g, 11.55 mmol, 73%) was made as a white solidfrom Intermediate I-35E (5.1 g, 15.8 mmol) via the same procedure asIntermediate I-28F. ¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (s, 1H), 7.10 (d,J=2.0 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.02 (s, 1H), 3.82 (d, J=1.8 Hz,2H); LC-MS: method H, RT=0.84 min, MS (ESI) m/z: 261.0 and 263.0 (M+H)⁺.

Intermediate I-35G: 7-bromo-5-chloroquinoxalin-2(1H)-one

Intermediate I-35G (3.40 g, 13.10 mmol, 70%) was made as an off-whitesolid from Intermediate I-35F (4.85 g, 18.5 mmol) via the same procedureas Intermediate I-28G. ¹H NMR (400 MHz, DMSO-d₆) δ 7.76 (s, 1H), 7.21(d, J=2.2 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H); LC-MS: method H, RT=1.08 min,MS (ESI) m/z: 259.1 and 261.1 (M+H)⁺.

Intermediate I-35H: 7-bromo-5-chloro-2-methoxyquinoxaline

Intermediate I-35H (2.13 g, 7.79 mmol, 86%) was made as a yellow solidfrom Intermediate I-35G (2.34 g, 9.02 mmol) via the same procedure asIntermediate I-28H. ¹H NMR (400 MHz, chloroform-d) δ 8.55 (s, 1H), 7.98(d, J=2.2 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 4.12 (s, 3H); LC-MS: methodH, RT=1.07 min, MS (ESI) m/z: 273.1 and 275.1 (M+H)⁺.

Intermediate I-35I: 5-chloro-2-methoxy-7-vinylquinoxaline

To a vial charged with a stirring bar was added Intermediate I-35H (0.7g, 2.56 mmol), potassium vinyltrifluoroborate (0.377 g, 2.82 mmol),cesium carbonate (1.668 g, 5.12 mmol),(s)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.159 g, 0.256 mmol)and diacetoxypalladium (0.029 g, 0.128 mmol). After applying vacuum andrefilling with N₂ 3 times, DMF (10 mL) was added and N₂ was bubbledthrough the solution for 10 minutes. The vial was sealed, stirred atroom temperature for 10 minutes, and then heated at 80° C. for 3 h.After cooling to room temperature, the reaction mixture was diluted with60 mL of EtOAc, washed with water and brine, dried over Na₂SO₄, filteredand concentrated. The crude product was purified by flash chromatography(0-50% EtOAc/Hexane in 12 minutes, 50-100% EtOAc/hexane in 6 minutes, 40g silica gel column) to give the title compound (470 mg, 2.130 mmol, 83%yield) as an off-white solid. ¹H NMR (400 MHz, chloroform-d) δ 8.51 (s,1H), 7.79 (d, J=2.0 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 6.83 (dd, J=17.5,10.9 Hz, 1H), 5.96 (d, J=17.4 Hz, 1H), 5.48 (d, J=11.0 Hz, 1H), 4.12 (s,3H); LC-MS: method H, RT=1.02 min, MS (ESI) m/z: 221.1.

Intermediate I-35J: 8-chloro-3-methoxyquinoxaline-6-carbaldehyde

In a round bottom flask charged with a stirring bar, Intermediate I-351(470 mg, 2.130 mmol) was dissolved in THF (20 mL)/water (6 mL), andtreated with sodium periodate (1367 mg, 6.39 mmol) and osmium tetroxide(4% by wt. in water) (0.271 mL, 0.043 mmol). The mixture was stirred atroom temperature for 4 h, and then reaction mixture was diluted byadding 40 mL of EtOAc and 20 mL of water. The organic phase was washedwith saturated Na₂S₂O₃ (aqueous, 3×) and brine, dried over Na₂SO₄, andfiltered. The filtrate was concentrated on a rotary evaporator to givethe title compound (457 mg, 2.053 mmol, 96% yield) as a yellow solid. ¹HNMR (400 MHz, chloroform-d) δ 10.17 (s, 1H), 8.67 (s, 1H), 8.27 (d,J=1.8 Hz, 1H), 8.16 (d, J=1.8 Hz, 1H), 4.17 (s, 3H); LC-MS: method H,RT=0.88 min, MS (ESI) m/z: 223.2.

Intermediate I-35K: (8-chloro-3-methoxyquinoxalin-6-yl)methanol

In a round bottom flask charged with a stirring bar, Intermediate I-35J(421 mg, 1.89 mmol) was dissolved in toluene (10 mL) and mixed withsodium triacetoxyborohydride (882 mg, 4.16 mmol). The mixture wasstirred at 60° C. for 4 h. After cooling to room temperature, thesolvent was removed on a rotary evaporator. The residue was dissolved in30 mL of EtOAc and 20 mL of water. The organic phase was washed withbrine, dried over Na₂SO₄, filtered and concentrated on a rotaryevaporator to give the title compound (0.415 g, 1.847 mmol, 98% yield)as an off-white solid. ¹H NMR (400 MHz, chloroform-d) δ 8.55 (s, 1H),7.79-7.75 (m, 1H), 7.70 (d, J=1.8 Hz, 1H), 4.89 (s, 2H), 4.12 (s, 3H),1.94 (br s, 1H); LC-MS: method H, RT=0.75 min, MS (ESI) m/z: 225.2.

Intermediate I-35

A microwave tube was charged with Pd₂(dba)₃ (48.9 mg, 0.053 mmol),X-Phos (102 mg, 0.214 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (814 mg,3.21 mmol), and potassium acetate (315 mg, 3.21 mmol). The tube wascapped and then evacuated and backfilled with argon 3 times.Intermediate I-35K (240 mg, 1.068 mmol) in 1,4-dioxane (10 mL) was addedvia syringe, followed by flushing the reaction mixture with N₂ for 10minutes. The reaction mixture was heated at 110° C. in a microwavereactor for 30 minutes. After cooling to room temperature, the reactionmixture was concentrated in vacuo and the residue was purified by flashchromatography (40 g silica gel, 0-100% EtOAc, then 0-10% MeOH/DCM) togive Intermediate I-35 (121 mg, 0.517 mmol, 48.4% yield) as a greysolid. LC-MS: method H, RT=0.75 min, MS (ESI) m/z: 235.2.

Intermediate I-362-methoxy-6,7-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

Intermediate I-36A: 2-bromo-3,4-dimethyl-6-nitroaniline

From commercially available 4,5-dimethyl-2-nitroaniline (5.76 g, 34.7mmol), Intermediate I-36A was prepared as a yellow solid (7.78 g, 31.7g, 114%) via the same procedure as Intermediate I-28A. ¹H NMR (400 MHz,DMSO-d₆) δ 7.90 (s, 1H), 7.11 (br s, 2H), 2.38 (s, 3H), 2.26 (s, 3H);LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 245.1 and 247.0 (M+H)⁺.

Intermediate I-36B: t-butylN-(2-bromo-3,4-dimethyl-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate

Intermediate I-36B (9.2 g, 19.2 mmol, 65.1%) was made as a yellow solidfrom Intermediate I-36A (7.78 g, 20.66 mmol) via the same procedure asIntermediate I-28B. ¹H NMR (400 MHz, chloroform-d) δ 7.83 (s, 1H), 2.51(s, 3H), 2.46 (s, 3H), 1.41 (s, 18H); LC-MS: method J, RT=1.03 min, MS(ESI) m/z: 445.1 and 447.0 (M+H)⁺.

Intermediate I-36C: tert-butyl(2-bromo-3,4-dimethyl-6-nitrophenyl)carbamate

Intermediate I-36C (6.6 g, 19.1 mmol, 93%) was made as a yellow solidfrom Intermediate I-36B (9.2 g, 1.30 mmol) via the same procedure asIntermediate I-28C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (br s, 1H), 7.80(s, 1H), 2.42 (s, 3H), 2.39 (s, 3H), 1.50-1.22 (m, 9H); LC-MS: method J,RT=0.88 min, MS (ESI) m/z: 245.0 and 247.0 (M+H-100)⁺.

Intermediate I-36D: methyl2-((2-bromo-3,4-dimethyl-6-nitrophenyl)(tert-butoxycarbonyl)amino)acetate

Intermediate I-36D (3.21 g, 7.69 mmol, 87%) was made as an orange oilfrom Intermediate I-36C (3.05 g, 8.84 mmol) via the same procedure asIntermediate I-28D. LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 317.0and 319.1 (M+H-100)⁺.

Intermediate I-36E: methyl2-((2-bromo-3,4-dimethyl-6-nitrophenyl)amino)acetate

Intermediate I-36E (2.43 g, 7.67 mmol, 100%) was made as a brown solidfrom Intermediate I-36D (3.2 g, 7.67 mmol) via the same procedure asIntermediate I-28E. LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 317.0and 319.0 (M+H)⁺.

Intermediate I-36F: 5-bromo-6,7-dimethyl-3,4-dihydroquinoxalin-2(1H)-one

Intermediate I-36F (1.69 g, 6.62 mmol, 86%) was made as a white solidfrom Intermediate I-36E (2.43 g, 7.67 mmol) via the same procedure asIntermediate I-28F. LC-MS: method H, RT=1.04 min, MS (ESI) m/z: 255.1and 257.0 (M+H)⁺.

Intermediate I-36G: 5-bromo-6,7-dimethylquinoxalin-2(1H)-one

Intermediate I-36G (1.12 g, 4.43 mmol, 86%) was made as a white solidfrom Intermediate I-36F (1.26 g, 4.94 mmol) via the same procedure asIntermediate I-28G. LC-MS: method H, RT=1.03 min, MS (ESI) m/z: 253.0and 255.1 (M+H)⁺.

Intermediate I-36H: 5-bromo-2-methoxy-6,7-dimethylquinoxaline

Intermediate I-36H (0.79 g, 2.97 mmol, 67.2%) was made as a white solidfrom Intermediate I-36G (1.12 g, 4.43 mmol) via the same procedure asIntermediate I-28H. ¹H NMR (400 MHz, chloroform-d) δ 8.48 (s, 1H), 7.61(s, 1H), 4.10 (s, 3H), 2.61 (s, 3H), 2.53 (s, 3H); LC-MS: method H,RT=1.19 min, MS (ESI) m/z: 267.0 and 268.8 (M+H)⁺.

Intermediate I-36

Intermediate I-36 (0.50 g, 2.14 mmol, 72.5%) was made as a brown solidfrom Intermediate I-36H (0.79 g, 2.96 mmol) via the same procedure asIntermediate I-281. LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 232.9(M+H-82)⁺.

Intermediate I-37 2(5-fluoro-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-6-yl)methanol

Intermediate I-37A: 4-bromo-6-chloro-3-fluoro-2-nitroaniline

A mixture of 4-bromo-3-fluoro-2-nitroaniline (1.0 g, 4.26 mmol), NCS(0.710 g, 5.32 mmol) in DMF (10 mL) was heated to 100° C. for 1 h. Aftercooling to room temperature, the reaction mixture was diluted by adding40 mL of DCM and 30 mL of water. After shaking and separation, aqueouslayer was extracted with DCM (20 mL×2). Then organic phases werecombined and washed with brine, dried over Na₂SO₄, filtered concentratedon a rotary evaporator, dried on a high vacuum pump to give4-bromo-6-chloro-3-fluoro-2-nitroaniline (1.22 g, 4.53 mmol, 106% yield)as brown oil. ¹H NMR (400 MHz, chloroform-d) δ 7.64 (d, J=6.4 Hz, 1H),6.02 (br s, 2H); ¹⁹F NMR (376 MHz, chloroform-d) δ −109.56 (s, 1F)

Intermediate I-37B: t-butylN-(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate

Intermediate I-37A (1.22 g, 4.53 mmol) was dissolved in THF (10 mL) andmixed with di-tert-butyl dicarbonate (1.976 g, 9.06 mmol) at roomtemperature, DMAP (0.055 g, 0.453 mmol) was added. The mixture wasstirred at room temperature overnight. the next day, solvent was removedon a rotary evaporator and residue was purified by flash chromatographyfor purification (40 g silica gel column, 0-50% EtOAc/Hexane gradient)to give the title compound (1.141 g, 2.429 mmol, 53.7% yield) as a whitesolid. ¹H NMR (400 MHz, chloroform-d) δ 7.86 (d, J=6.4 Hz, 1H), 1.43 (s,18H); ¹⁹F NMR (376 MHz, chloroform-d) δ −114.28 (s, 1F).

Intermediate I-37C: tert-butyl(4-bromo-6-chloro-3-fluoro-2-nitrophenyl)carbamate

Intermediate I-37C (0.85 g, 2.3 mmol, 95%) was made as a yellow solidfrom Intermediate I-37B (9.2 g, 1.30 mmol) via the same procedure asIntermediate I-28C. ¹H NMR (400 MHz, chloroform-d) δ 7.82 (d, J=6.4 Hz,1H), 6.61 (br s, 1H), 1.50 (s, 9H); ¹⁹F NMR (376 MHz, chloroform-d) δ−112.58 (br s, 1F).

Intermediate I-37D: methyl2-((4-bromo-6-chloro-3-fluoro-2-nitrophenyl)(tert-butoxycarbonyl)amino)acetate

Intermediate I-37D (0.68 g, 1.55 mmol, 68%) was made as a colorless oilfrom Intermediate I-37C (0.85 g, 2.30 mmol) via the same procedure asIntermediate I-28D. ¹H NMR (400 MHz, chloroform-d) δ 7.85 (d, J=6.4 Hz,1H), 4.44 (d, J=17.4 Hz, 1H), 3.96-3.89 (m, 1H), 3.74 (s, 3H), 1.40 (s,9H); ¹⁹F NMR (376 MHz, chloroform-d) δ −114.08 (s, 1F); LC-MS: method H,RT=1.05 min, MS (ESI) m/z: 341.1 and 343.0 (M+H-100)⁺.

Intermediate I-37E: methyl2-((4-bromo-6-chloro-3-fluoro-2-nitrophenyl)amino)acetate

Intermediate I-37E (0.53 g, 1.55 mmol, 100%) was made as brown oil fromIntermediate I-37D (0.68 g, 1.55 mmol) via the same procedure asIntermediate I-28E. LC-MS: method H, RT=1.01 min, MS (ESI) m/z: 341.1and 343.0 (M+H)⁺.

Intermediate I-37F:7-bromo-5-chloro-8-fluoro-3,4-dihydroquinoxalin-2(1H)-one

Intermediate I-37F (0.34 g, 1.22 mmol, 79%) was made as a yellow oilfrom Intermediate I-37E (0.53 g, 1.55 mmol) via the same procedure asIntermediate I-28F. ¹H NMR (400 MHz, Acetone) δ 9.51 (br s, 1H), 7.17(d, J=6.4 Hz, 1H), 5.72 (br s, 1H), 4.05-3.97 (m, 2H); ¹⁹F NMR (376 MHz,Acetone) δ 47.90 (br s, 1F); LC-MS: method I, RT=1.17 min, MS (ESI) m/z:279.0 and 281.1 (M+H)⁺.

Intermediate I-37G: 7-bromo-5-chloro-8-fluoroquinoxalin-2(1H)-one

Intermediate I-37G (0.31 g, 1.10 mmol, 90%) was made as a yellow solidfrom Intermediate I-37F (0.34 g, 1.22 mmol) via the same procedure asIntermediate I-28G. LC-MS: method H, RT=0.77 min, MS (ESI) m/z: 277.0and 279.0 (M+H)⁺.

Intermediate I-37H: 7-bromo-5-chloro-8-fluoro-2-methoxyquinoxaline

Intermediate I-37G (306 mg, 1.103 mmol) was treated with POCl₃ (3 mL,32.2 mmol) and heated to refluxing for 1 hour. After cooling to roomtemperature, extra POCl₃ was removed on a rotary evaporator and theresidue was dried on HVAC for 1 hour. Then the material was dissolved inanhydrous MeOH (10 mL) and K₂CO₃ (517 mg, 3.74 mmol) was added. Afterstirring at room temperature for 10 minutes, the mixture was refluxedfor 2 h. Then reaction mixture was cooled to room temperature. Most ofMeOH was removed on a rotary evaporator and residue was dissolved in 30mL of EtOAc and 15 mL of H₂O. After separation, organic phase was washedwith brine, dried over Na₂SO₄, filtered and concentrated on a rotaryevaporator. The residue was purified by flash chromatography column (40g silica gel, 0-100% EtOAc/Hexane gradient). Removing solvent gave7-bromo-5-chloro-8-fluoro-2-methoxyquinoxaline (85 mg, 0.292 mmol, 26.4%yield) as a yellow solid. ¹H NMR (400 MHz, chloroform-d) δ 8.60 (s, 1H),7.82 (d, J=6.2 Hz, 1H), 4.18 (s, 3H); ¹⁹F NMR (376 MHz, chloroform-d) δ−119.01 (s, 1F); LC-MS: method H, RT=1.05 min, MS (ESI) m/z: 291.0 and293.1 (M+H)⁺.

Intermediate I-37I: 5-chloro-8-fluoro-2-methoxy-7-vinylquinoxaline

To a vial charged with a stirring bar was added Intermediate I-37H (83mg, 0.285 mmol), potassium trifluoro(vinyl)borate (36.2 mg, 0.270 mmol),cesium carbonate (186 mg, 0.569 mmol),(s)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (35.5 mg, 0.057 mmol)and Pd(OAc)₂ (6.39 mg, 0.028 mmol). After applying vacuum and refillingwith N₂ 3 times, DMF (1.0 mL) was added and the mixture was degassedwith bubbling N₂ for 10 minutes. The vial was sealed and the reactionmixture was stirred at room temperature for 10 minutes, then heated at120° C. for 2 h. After cooling to room temperature, the reaction mixturewas diluted by adding 20 mL of EtOAc and washed with water and brine,dried over Na₂SO₄ and filtered. Removing solvent gave crude product thatwas purified by flash chromatography (24 g silica gel column, 0-100%EtOAc/Hexane gradient in 10 minutes). Removing solvent gave5-chloro-8-fluoro-2-methoxy-7-vinylquinoxaline (43 mg, 0.180 mmol, 63.3%yield) as a yellow solid. LC-MS: method H, RT=1.05 min, MS (ESI) m/z:239.0 (M+H)⁺.

Intermediate I-37J:8-chloro-5-fluoro-3-methoxyquinoxaline-6-carbaldehyde

Intermediate I-37I (43 mg, 0.180 mmol) was dissolved in THF (3mL))/water (1 mL). Sodium periodate (116 mg, 0.541 mmol) was added,followed by osmium tetroxide (0.023 mL, 3.60 μmol). The mixture wasstirred at room temperature for 6 h. Then the reaction mixture wasdiluted by adding 30 mL of EtOAc and 20 mL of water. After separation,organic phase was washed with saturated Na₂S₂O₃ (aqueous) 3 times,brine, dried over Na₂SO₄ and filtered. Concentration on a rotaryevaporator gave 8-chloro-5-fluoro-3-methoxyquinoxaline-6-carbaldehyde(32 mg, 0.133 mmol, 73.8% yield) as light yellow solid. ¹H NMR (400 MHz,chloroform-d) δ 10.58 (s, 1H), 8.70 (s, 1H), 8.07 (d, J=5.9 Hz, 1H),4.22 (s, 3H); LC-MS: method H, RT=0.90 min, MS (ESI) m/z: 241.0 (M+H)⁺.

Intermediate I-37K: (8-chloro-5-fluoro-3-methoxyquinoxalin-6-yl)methanol

Intermediate I-37J (32 mg, 0.133 mmol) was dissolved in toluene (1 mL)and mixed with sodium triacetoxyborohydride (62.0 mg, 0.293 mmol). Themixture was stirred at 60° C. for 4 hour. Then reaction mixture wascooled to room temperature, solvent was removed on a rotary evaporator.The residue was dissolved in 20 mL of EtOAc and 10 mL of water. Afterseparation, organic phase was washed with brine, passed over Na₂SO₄,concentrated on a rotary evaporator to give(8-chloro-5-fluoro-3-methoxyquinoxalin-6-yl)methanol (26 mg, 0.107 mmol,81% yield) as a solid. ¹H NMR (400 MHz, chloroform-d) δ 8.58 (s, 1H),7.80 (d, J=6.2 Hz, 1H), 4.97 (d, J=4.4 Hz, 2H), 4.17 (s, 3H), 2.10-2.03(m, 1H); LC-MS: method H, RT=0.75 min, MS (ESI) m/z: 243.0 (M+H)⁺.

Intermediate I-37

In a microwave tube was charged with Pd₂(dba)₃ (4.91 mg, 5.36 μmol),XPhos (10.22 mg, 0.021 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (82 mg,0.321 mmol) and potassium acetate (31.5 mg, 0.321 mmol). The microwavetube was capped, evacuated and backfilled with argon (this sequence wascarried out two times). Intermediate I-37J (26 mg, 0.107 mmol) in1,4-dioxane (1 ml) was added via syringe, followed by flushing thereaction mixture with N₂ for 10 minutes. The microwave tube was sealedand the reaction mixture was heated at 130° C. in a microwave reactorfor 30 minutes. After cooling to room temperature, the reaction mixturewas removed. The crude material Intermediate I-37 was used withoutpurification in the next step. LC-MS: method H, RT=0.65 min, MS (ESI)m/z: 253.1 (M+H)⁺.

Intermediate I-383-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline-6-carbonitrile

Intermediate I-38A:8-bromo-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile

Intermediate I-38A was synthesized from 4-amino-3-nitrobenzonitrile viathe route described for Intermediate I-28. LC-MS: method I, RT=0.94 min,MS (ESI) m/z: 252.0 and 253.9 (M+H)⁺.

Intermediate I-38B: 8-bromo-3-oxo-3,4-dihydroquinoxaline-6-carbonitrile

In a round bottom flask charged with a stirring bar, Intermediate I-38A(394 mg, 1.563 mmol) was suspended in DMF (10 mL), and manganese dioxide(1359 mg, 15.63 mmol) was added. The mixture was stirred at roomtemperature for 60 minutes. LCMS showed starting material remained.Another 10 equivalents of manganese dioxide (1359 mg, 15.63 mmol) wasadded, and the mixture was stirred at room temperature overnight. Thenext day, the solid was filtered and solvent was removed on a rotaryevaporator and dried on HVAC to give the title compound (100 mg, 0.400mmol, 25.6% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32(s, 1H), 7.95 (d, J=2.6 Hz, 1H), 7.65 (s, 1H); LC-MS: method A, RT=2.42min, MS (ESI) m/z: 248.0 and 250.0 (M+H)⁺.

Intermediate I-38

Intermediate I-38 was synthesized in two steps from Intermediate I-38Bvia the route described in Intermediate I-28. LC-MS: method A, RT=0.97min, MS (ESI) m/z: 230.1 (M+H)⁺ of boronic acid.

Intermediate I-39 Ethyl2-((2-bromo-4-methylbenzo[d]thiazol-6-yl)oxy)acetate

Intermediate I-39 was made from Intermediate I-40 following theprocedure described in I-49. ¹H NMR (400 MHz, chloroform-d) δ 7.08 (d,J=2.2 Hz, 1H), 6.95-6.92 (m, 1H), 4.66 (s, 2H), 4.29 (q, J=7.3 Hz, 2H),2.67 (s, 3H), 1.31 (t, J=7.2 Hz, 3H; LC-MS: method H, RT=1.37 min, MS(ESI) m/z: 330.0 and 332.0.

Intermediate I-40 2-bromo-4-methylbenzo[d]thiazol-6-ol

Intermediate I-3 (100 mg, 0.387 mmol) was solvated in DCM (3.87 mL) andcooled to 0° C. Boron tribromide (1.0 M in Hexanes) (0.415 mL, 0.415mmol) was slowly added dropwise. After 1 h of stirring, the reactionmixture was allowed to thaw to room temperature. Once at roomtemperature, the reaction mixture was recooled to 0° C. and quenchedwith saturated NH₄Cl. The resulting mixture was extracted twice with DCMand the organic phase was dried over MgSO₄, filtered and concentrated.The crude product was purified by ISCO (12 g, 0-30% EtOAc/Hexanes, 18min. Product at 18%) to give clean Intermediate I-40 (54 mg, 0.221 mmol,57.1% yield) as a white solid. LC-MS: Method H, RT=1.10 min, MS (ESI)m/z: 244.0, 246.0 (M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.06 (d, J=2.2Hz, 1H), 6.79 (s, 1H), 2.57 (s, 1H).

Intermediate I-41 2-bromo-4,5-difluoro-6-methoxybenzo[d]thiazole

Intermediate I-41A: 2,3-difluoro-4-methoxyaniline

Degussa grade Pd/C (1.125 g, 1.058 mmol) was added to a 250 mL roundbottom flask previously purged with argon. The Pd was carefully wettedwith a few milliliters of MeOH before the full amount of solvent (42.3ml) was added. The head space of the flask was evacuated until thesolvent began to slightly bubble and then back-filled 3× with N₂.2,3-difluoro-1-methoxy-4-nitrobenzene (2.0 g, 10.58 mmol) was added tothe black suspension, and a balloon of Hz gas was attached. Theheterogeneous mixture was sparged with H₂ for 30 min, before beingallowed to stir under an atmosphere of H₂ for an additional 4 h. Thereaction mixture was then filtered over celite to remove Pd/C. Thecelite was rinsed with EtOAc, and the filtrate was concentrated toafford Intermediate I-41A (1.63 g, 10.24 mmol, 97% yield) as a purplesolid. LC-MS: Method H, RT=0.83 min, MS (ESI) m/z: 160.1 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 6.59 (td, J=8.6, 2.2 Hz, 1H), 6.49-6.43 (m,1H), 3.83 (s, 3H), 3.51 (br. s., 2H).

Intermediate I-41B: 4,5-difluoro-6-methoxybenzo[d]thiazol-2-amine

To a solution of Intermediate I-41A (1.63 g, 10.24 mmol) in acetonitrile(51.2 ml) was added ammonium thiocyanate (1.014 g, 13.32 mmol). Themixture was stirred at room temperature for 10 min followed by theaddition of benzyltrimethylammonium tribromide (4.39 g, 11.27 mmol).After 16 h, the reaction mixture was concentrated down and retaken inDCM. The organic phase was washed with saturated NaHCO₃, concentratedand purified by ISCO (120 g, 0-100% EtOAc/Hexanes, 16 min. Product from55%-100%) to afford Intermediate I-41B (398 mg, 1.843 mmol, 18% yield).LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 217.2 (M+H)⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 6.96 (dd, J=6.9, 2.1 Hz, 1H), 5.19 (br. s., 2H),3.92 (s, 3H).

Intermediate I-41

To a solution of copper (II) bromide (289 mg, 1.295 mmol) andIntermediate I-41B (280 mg, 1.295 mmol) in acetonitrile (10 mL) wasadded t-Butyl nitrite (0.222 mL, 1.684 mmol) at room temperature. After30 min, the crude mixture was diluted with EtOAc and washed with 1 MHCl. The organic phase was dried over MgSO₄, filtered, concentrated andpurified by ISCO flash chromatography (0-20% EtOAc/Hex, 19 min, 40 gsilica gel cartridge. Product from 12% to 20%) to afford IntermediateI-41 (271 mg, 0.968 mmol, 74.7% yield) as an off-white solid. LC-MS:Method H, RT=1.21 min, MS (ESI) m/z: 280.1, 282.0 (M+H)⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.11 (dd, J=6.6, 2.0 Hz, 1H), 3.98 (s, 3H).

Intermediate I-42 2-bromo-4,5-difluorobenzo[d]thiazol-6-ol

A solution of Intermediate I-41 (220 mg, 0.785 mmol) solvated in DCM (20ml) was cooled to 0° C. A solution of BBr₃ (1.0 M hexanes) (1.571 ml,1.571 mmol) was then added dropwise. After 5 min, the mixture wasallowed to thaw to room temperature. After an additional 18 h, thereaction mixture was quenched with 1 M HCl (20.0 mL) and stirredvigorously for 20 min to fully cleave the boronate complex. The mixturewas diluted with EtOAc and extracted. The organic phase was dried overMgSO₄, filtered and concentrated to give Intermediate I-42 (208 mg,0.785 mmol, 100% yield) which was taken forward without furtherpurification. LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 266.0, 268.0(M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.24 (dd, J=7.2, 2.1 Hz, 1H).

Intermediate I-43 2-bromo-4-chloro-5-fluoro-6-methoxybenzo[d]thiazole

Intermediate I-43A: 2-chloro-3-fluoro-4-methoxy-1-nitrobenzene

To a 0° C. solution of 1-chloro-2-fluoro-3-methoxybenzene (1.606 g, 10mmol) in acetic acid (5.00 ml) was added fuming nitric acid (0.933 ml,20.00 mmol) followed by the dropwise addition of sulfuric acid (2.132ml, 40.0 mmol). After 30 min, the reaction mixture was poured into waterand diluted with ethyl acetate. The organic phase was separated andwashed 2× with saturated NaHCO₃ followed by a final brine wash. Theorganic solution was then dried over MgSO₄, filtered, concentrated andpurify by ISCO (120 g, 10-50% EtOAc/Hexanes, 25 min. Desired regioisomereluted second) affording Intermediate I-43A (1.10 g, 5.35 mmol, 53%yield) as a yellow solid. LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: NoIonization Observed (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (dd,J=9.2, 2.2 Hz, 1H), 6.95 (dd, J=9.4, 7.6 Hz, 1H), 4.00 (s, 3H).Regiochemistry confirmed through NMR analysis of both regioisomericproducts.

Intermediate I-43B: 2-chloro-3-fluoro-4-methoxyaniline

To a solution of Intermediate I-43A (1.10 g, 5.35 mmol) in MeOH (26.7mL, 0.2 M) was added NH₄Cl (5.72 g, 107 mmol) and zinc dust (3.50 g,53.5 mmol). The resulting mixture was allowed to stir at roomtemperature overnight. After 14 h, the MeOH solvent was removed invacuo. The resulting residue was diluted with EtOAc and saturated sodiumbicarbonate (0.2 M of each) and stirred vigorously for 1 hr and thenfiltered over celite. The organic layer was then separated, washed withbrine, dried over MgSO₄, filtered and concentrated to give IntermediateI-43B (710 mg, 4.04 mmol, 76% yield) as a dark brown solid. Thismaterial was taken on without further purification. LC-MS: Method H,RT=0.95 min, MS (ESI) m/z: 176.1, 178.1 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 6.76 (t, J=8.7 Hz, 1H), 6.49 (dd, J=9.0, 2.2 Hz, 1H),3.86 (br. s, 2H), 3.82 (s, 3H).

Intermediate I-43C: 4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2-amine

To a solution of Intermediate I-43B (820 mg, 3.74 mmol) in acetonitrile(18.700 mL) was added ammonium thiocyanate (370 mg, 4.86 mmol). Themixture was stirred at room temperature for 10 min and thenbenzyltrimethylammonium tribromide (1457 mg, 3.74 mmol) was added. Theresulting heterogeneous mixture was stirred vigorously overnight. After16 h, the reaction mixture was concentrated and retaken in 30 mLsaturated NaHCO₃. This suspension was stirred vigorously and thenfiltered. The collected solid was washed with water and transferred to anew flask using acetone. This solution was concentrated in vacuo toafford Intermediate I-43C (863 mg, 3.67 mmol, 99% yield) as a yellowsolid. This material was taken on without further purification. LC-MS:Method H, RT=0.95 min, MS (ESI) m/z: 233.1, 235.1 (M+H)⁺. ¹H NMR (400MHz, METHANOL-d₄) δ 7.34 (d, J=7.5 Hz, 1H), 3.88 (s, 3H).

Intermediate I-43

To a solution of copper (II) bromide (835 mg, 3.74 mmol) andIntermediate I-43C (870 mg, 3.74 mmol) in acetonitrile (18.700 mL) wasadded t-butyl nitrite (0.642 mL, 4.86 mmol) at room temperature. After30 min, the reaction mixture was diluted with EtOAc and washed with 1 MHCl followed by 1 M K₂HPO₄, then brine. The organic phase wasconcentrated and purified by ISCO flash chromatography (0-20% EtOAc/Hexover 30 min, 120 g silica gel cartridge-product at 10%) to affordIntermediate I-43 (723 mg, 2.267 mmol, 60.6% yield) as a yellow solid.LC-MS: Method H, RT=1.23 min, MS (ESI) m/z: 295.9, 297.9, 299.9 (M+H)⁺.¹H NMR (400 MHz, CHLOROFORM-d) δ 7.23 (d, J=7.3 Hz, 1H), 3.96 (s, 3H).

Intermediate I-44 2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-ol

To a solution of Intermediate I-43 (72 mg, 0.243 mmol) in toluene (2428μl) was added AlCl₃ (97 mg, 0.728 mmol) and the mixture was heated toreflux. After 2 h, the solution was allowed to cool to room temperature,and the resulting mixture was diluted with 1 M HCl followed by EtOAc.The organic phase was separated, dried over MgSO₄, filtered andconcentrated to give Intermediate I-44 (38 mg, 0.135 mmol, 55.4% yield)as a brown solid. The isolated material was taken on without furtherpurification. LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 281.9, 284.0,285.9 (M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.39 (d, J=7.7 Hz, 1H).

Intermediate I-45 2-bromo-5-fluoro-6-methoxy-4-methylbenzo[d]thiazole

Intermediate I-45A: 1-chloro-3-fluoro-2-methoxy-4-methyl-5-nitrobenzene

A solution of 1-chloro-3-fluoro-2-methoxy-4-methylbenzene (1 g, 5.73mmol) in acetic acid (2.86 ml) was cooled to 0° C. To this cooledsolution was added fuming nitric acid (0.535 ml, 11.45 mmol) followed bysulfuric acid (1.221 ml, 22.91 mmol) dropwise. After 30 min, thereaction mixture was poured into ice water and extracted with ethylacetate. The organic phase was washed with 1 M K₂HPO₄ and thenconcentrated in vacuo to give Intermediate I-45A (1.26 g, 5.16 mmol, 90%yield) as a dark orange oil. This material was taken forward withoutfurther purification. LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: NoneObserved (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.91 (d, J=2.2 Hz,1H), 4.08 (d, J=2.4 Hz, 3H), 2.50 (d, J=2.9 Hz, 3H).

Intermediate I-45B: 5-chloro-3-fluoro-4-methoxy-2-methylaniline

A 250 mL round bottom flask containing Intermediate I-45A (1.26 g, 5.74mmol) was evacuated and back-filled with N₂. Degussa grade Pd/C (0.611g, 0.574 mmol) was then added to the orange oil. This mixture wascarefully wet with a few mL of MeOH before the full solvent volume (28.7ml) was added. The head space of the flask was evacuated until thesolvent began to slightly bubble and then back-filled with N₂. A balloonof hydrogen gas was attached and the mixture was sparged with H₂ forabout 15 minutes through a vent needle. The vent was removed and thereaction mixture was stirred vigorously under an atmosphere of H₂overnight. After 14 h, the reaction mixture was filtered over Celite andrinsed with EtOAc to afford Intermediate I-45B (890 mg, 5.74 mmol, 100%yield) as a tan solid. This material was taken on to the next reactionwithout further purification. LC-MS: Method H, RT=0.71 min, MS (ESI)m/z: 156.0 (M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.18-6.95 (m, 2H),3.88 (s, 3H), 2.27 (d, J=2.4 Hz, 3H).

Intermediate I-45C: 5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-amine

To a solution of Intermediate I-45B (1.03 g, 6.64 mmol) in acetonitrile(33.2 ml) was added ammonium thiocyanate (0.657 g, 8.63 mmol) followedby benzyltrimethylammonium tribromide (2.59 g, 6.64 mmol). The resultingmixture was stirred vigorously for 4 h before being diluted withsaturated NaHCO₃ and extracted 2× with DCM. The organic phase was driedover MgSO₄, filtered and concentrated in vacuo to afford IntermediateI-45C (920 mg, 4.33 mmol, 65.3% yield). This material was taken onwithout further purification. LC-MS: Method H, RT=0.84 min, MS (ESI)m/z: 213.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.39 (br. s., 2H), 7.35(d, J=8.1 Hz, 1H), 3.80 (s, 3H), 2.33 (d, J=2.2 Hz, 3H).

Intermediate I-45

To a heterogeneous solution of Intermediate I-45C (920 mg, 4.33 mmol) inacetonitrile (43.3 ml) was added copper (II) bromide (0.968 g, 4.33mmol) followed by t-butyl nitrite (0.745 ml, 5.64 mmol). After 30 min,the reaction mixture was diluted with 1 M HCl and extracted 2× withEtOAc. The organic phase was dried over MgSO₄, filtered over celite,concentrated and purified by ISCO (120 g, 0-10% EtOAc/Hexanes, 35 min.Product at 4%) to afford Intermediate I-45 (750 mg, 2.72 mmol, 62.7%yield) as a beige solid. LC-MS: Method H, RT=1.28 min, MS (ESI) m/z:276.0, 278.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.15 (d, J=7.5 Hz,1H), 3.93 (s, 3H), 2.61 (dd, J=2.4, 0.4 Hz, 3H).

Intermediate I-46 2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-ol

To a solution of Intermediate I-45 (155 mg, 0.561 mmol) in toluene (2807μl) was added AlCl₃ (225 mg, 1.684 mmol). The mixture was heated to 90°C. for 30 min and then allowed to cool room temperature. The resultingmixture was diluted with EtOAc and washed 2× with 1 M HCl followed byBrine. The organic phase was dried over MgSO₄, filtered and concentratedin vacuo to afford Intermediate I-46 (123 mg, 0.399 mmol, 71.1% yield)as a brown solid. This material was taken on without furtherpurification. LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 262.0, 264.0(M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.23 (dd, J=7.9, 0.4 Hz, 1H),2.54 (dd, J=2.4, 0.4 Hz, 3H).

Intermediate I-47 2-bromo-6-methoxy-4,5-dimethylbenzo[d]thiazole

Intermediate I-47A: 4-methoxy-2,3-dimethylaniline

A 250 mL round bottom flask containing1-methoxy-2,3-dimethyl-4-nitrobenzene (1 g, 5.52 mmol) was evacuated andback-filled with N₂. The flask was then charged with Degussa grade Pd/C(0.587 g, 0.552 mmol). This mixture was carefully wet with a fewmilliliters of MeOH before the full solvent volume (27.6 ml) was added.The head space of the flask was evacuated until the solvent began toslightly bubble and then back-filled with N₂. A balloon of hydrogen gaswas attached and the mixture was sparged with H₂ for about 15 minutesthrough a vent needle. The vent was removed and the reaction mixture wasstirred vigorously under an atmosphere of H₂ overnight. After 14 h, thereaction mixture was filtered over celite and rinsed with EtOAc toafford Intermediate I-47B (820 mg, 5.42 mmol, 98% yield) as a dark brownsolid. This material was taken on to the next reaction without furtherpurification. LC-MS: Method H, RT=0.71 min, MS (ESI) m/z: 152.1 (M+H)⁺.¹H NMR (400 MHz, CHLOROFORM-d) δ 6.66-6.47 (m, 2H), 3.75 (s, 3H), 3.34(br. s., 2H), 2.17 (s, 3H), 2.10 (s, 3H).

Intermediate I-47B: 6-methoxy-4,5-dimethylbenzo[d]thiazol-2-amine

To a solution of Intermediate I-47A (100 mg, 0.661 mmol) in acetonitrile(18.700 mL) was added ammonium thiocyanate (370 mg, 4.86 mmol). Themixture was stirred at room temperature for 10 min and thenbenzyltrimethylammonium tribromide (1457 mg, 3.74 mmol) was added. After2 h of vigorous stirring, the reaction mixture was concentrated andretaken in 5 mL saturated NaHCO₃. This suspension was stirred vigorouslyand then filtered. The collected solid was washed with water andtransferred to a new flask using acetone. This solution was concentratedin vacuo to afford Intermediate I-47B (136 mg, 0.654 mmol, 99% yield) asa tan solid. This material was taken on without further purification.LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 209.2 (M+H)⁺. ¹H NMR (400MHz, METHANOL-d₄) δ 7.03 (s, 1H), 3.79 (s, 3H), 2.42 (s, 3H), 2.17 (s,3H).

Intermediate I-47

To a heterogeneous solution of crude Intermediate I-47B (136 mg, 0.65mmol) in acetonitrile (6600 μl) was added copper (II) bromide (145 mg,0.65 mmol) followed by t-butyl nitrite (113 μl, 0.858 mmol). After 30min, the reaction mixture was diluted with 1 M HCl and EtOAc. Theorganic phase was dried over MgSO₄, filtered, concentrated and purifiedby ISCO (24 g, 0-20% EtOAc/Hexanes, 25 min. Product at 5%) to affordIntermediate I-47 (45 mg, 0.165 mmol, 25.05% yield) as a beige solid.LC-MS: Method H, RT=1.34 min, MS (ESI) m/z: 272.1, 274.1 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.05 (s, 1H), 3.87 (s, 3H), 2.64 (s, 3H), 2.25(s, 3H).

Intermediate I-48 2-bromo-4,5-dimethylbenzo[d]thiazol-6-ol

To a solution of Intermediate I-47 (600 mg, 2.205 mmol) in toluene(22.000 mL) was added AlCl₃ (588 mg, 4.41 mmol). The mixture was heatedto 90° C. under an atmosphere of N₂ for 1 h. The solution was thencooled to room temperature and 22 mL of 1 M HCl was added. The resultingmixture was stirred vigorously at room temperature for 1 h. The solutionwas then filtered to collect the off-white solid which had precipitatedout of the mixture. These solids were washed with water, retaken intoluene and concentrated in vacuo to afford Intermediate I-48 (350 mg,2.205 mmol, 61.5% yield), which was taken on without furtherpurification. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 258.0, 260.0(M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.06 (s, 1H), 2.57 (s, 3H), 2.24(s, 3H).

Intermediate I-49 methyl2((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)acetate

To a solution of Intermediate I-48 (240 mg, 0.930 mmol) solvated in DMF(9297 μl) was added methyl 2-bromoacetate (132 μl, 1.395 mmol) followedby K₂CO₃ (257 mg, 1.859 mmol). The resulting mixture was stirredvigorously at room temperature for 30 min, before being diluted EtOAc,filtered over celite, concentrated and purified by ISCO (40 g, 0-30%EtOAc/Hexanes, 19 min. Product at 15%) to afford Intermediate I-49 (268mg, 0.812 mmol, 87% yield) as a light pink solid. LC-MS: Method H,RT=1.29 min, MS (ESI) m/z: 333.0, 332.0 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 6.96 (s, 1H), 4.69 (s, 2H), 3.82 (s, 3H), 2.65 (s, 3H),2.33 (s, 3H).

Intermediate I-50 methyl2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propanoate (racemate)

To a solution of Intermediate I-48 (30 mg, 0.116 mmol) solvated in DMF(1162 μl) was added methyl 2-bromopropanoate (38.9 μl, 0.349 mmol)followed by K₂CO₃ (48.2 mg, 0.349 mmol). The mixture was stirredvigorously for 1.5 h before being diluted with EtOAc, filtered overcelite, concentrated and purified by ISCO (12 g, 0-30% EtOAc/Hexanes, 16min. Product at 15%) to afford Intermediate I-50 (rac) (37 mg, 0.107mmol, 92% yield) as a light pink solid. LC-MS: Method H, RT=1.31 min, MS(ESI) m/z: 344.1, 346.1 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.93(s, 1H), 4.76 (q, J=6.8 Hz, 1H), 3.76 (s, 3H), 2.64 (s, 3H), 2.31 (s,3H), 1.67 (d, J=6.6 Hz, 3H).

Intermediate I-512-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethanol

A solution of Intermediate I-49 (170 mg, 0.515 mmol) in toluene (3432μl) and THF (1716 μl) was cooled to −78° C. under an atmosphere of N₂.To this cold solution was added DIBAL-H (1 M in Toluene) (1.13 mL, 1.13mmol) dropwise. After 5 min of stirring, the reaction mixture wasallowed to thaw to room temperature. Once this solution reached roomtemperature, 5 mL of 1 M HCl was added. The resulting slurry was stirredvigorously for 1 hr to fully cleave the aluminate complexes. The mixturewas then diluted with EtOAc, extracted, washed with brine, dried overMgSO₄, filtered and concentrated. The crude product was purified by ISCO(40 g, 0-100% EtOAc/Hexanes, 19 min. Product at 47%) to afford2((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy) ethanol (156 mg, 0.516mmol, 100% yield) as an off-white, amorphous solid. LC-MS: Method H,RT=1.19 min, MS (ESI) m/z: 302.1, 304.1 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.08 (s, 1H), 4.15-4.09 (m, 2H), 4.06-3.99 (m, 2H), 2.65(s, 3H), 2.29 (s, 3H), 1.94 (t, J=6.3 Hz, 1H).

Intermediate I-52 Methyl2((2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-yl)oxy)acetate

To a solution of Intermediate I-46 (105 mg, 0.341 mmol) solvated in DMF(3405 μl) was added methyl 2-bromoacetate (48.4 μl, 0.511 mmol) followedby K₂CO₃ (94 mg, 0.681 mmol). The reaction mixture was stirredvigorously at room temperature for 1 h before being diluted with EtOAc,filtered over celite and concentrated. The crude material was purifiedby ISCO (24 g, 0-50% EtOAc/Hexanes, 20 min. Product at 18%) to affordIntermediate I-52 (81 mg, 0.242 mmol, 71% yield) as a pink solid. LC-MS:Method H, RT=1.20 min, MS (ESI) m/z: 334.0, 336.0 (M+H)⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.15 (d, J=7.5 Hz, 1H), 4.74 (s, 2H), 3.82 (s, 3H),2.62 (dd, J=2.4, 0.4 Hz, 3H).

Intermediate I-532-((2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol

This intermediate was prepared in a manner analogous to IntermediateI-51. Thus, Intermediate I-52 was reacted to afford Intermediate I-53(82% yield) as an off-white, amorphous solid. LC-MS: Method H, RT=1.09min, MS (ESI) m/z: 306.0, 308.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.19 (d, J=7.5 Hz, 1H), 4.20-4.15 (m, 2H), 4.02 (dt, J=6.2, 4.5 Hz, 2H),2.61 (d, J=2.4 Hz, 3H), 2.08 (t, J=6.4 Hz, 1H).

Intermediate I-54(2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)methanol

Intermediate I-54A: methyl 3-methoxy-2-methyl-6-nitrobenzoate

This intermediate was prepared in a manner analogous to IntermediateI-43A. Thus, methyl 3-methoxy-2-methylbenzoate was reacted to affordIntermediate I-54A (56% yield) as the major regioisomer isolated fromthe reaction mixture (second eluting on silica gel). LC-MS: Method H,RT=1.20 min, MS (ESI) m/z: None Observed (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.13 (d, J=9.0 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 3.97 (s,3H), 3.95 (s, 3H), 2.20 (s, 3H).

Intermediate I-54B: methyl 6-amino-3-methoxy-2-methylbenzoate

This intermediate was prepared in a manner analogous to IntermediateI-47A. Thus, Intermediate I-54A was reacted to afford Intermediate I-54B(100% yield) as a brown oil. LC-MS: Method H, RT=0.60 min, MS (ESI) m/z:196.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.82 (d, J=8.8 Hz, 1H),6.53 (dd, J=8.7, 0.6 Hz, 1H), 4.38 (br. s., 2H), 3.90 (s, 3H), 3.75 (s,3H), 2.26 (s, 3H).

Intermediate I-54C: methyl2-amino-6-methoxy-5-methylbenzo[d]thiazole-4-carboxylate

This intermediate was prepared in a manner analogous to IntermediateI-47B. Thus, Intermediate I-54B was reacted to afford Intermediate I-54C(60% yield) as a brown solid. LC-MS: Method H, RT=0.66 min, MS (ESI)m/z: 252.9 (M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.29 (s, 1H), 3.93(s, 3H), 3.84 (s, 3H), 2.17 (s, 3H).

Intermediate I-54D: methyl2-bromo-6-methoxy-5-methylbenzo[d]thiazole-4-carboxylate

This intermediate was prepared in a manner analogous to IntermediateI-47. Thus, Intermediate I-54C was reacted to afford Intermediate I-54D(70% yield) as a bright yellow solid. LC-MS: Method H, RT=0.99 min, MS(ESI) m/z: 315.7, 317.7 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.22(s, 1H), 4.03 (s, 3H), 3.90 (s, 3H), 2.29 (s, 3H).

Intermediate I-54

A solution of Intermediate I-54D (390 mg, 1.234 mmol) in toluene (8223μl) and THF (4112 μl) was cooled to −78° C. under an atmosphere of N₂.To this cooled solution was added DIBAL-H (1 M in toluene) (2714 μl,2.71 mmol) dropwise. After 5 min of stirring, the mixture was allowed tothaw to room temperature. Once at room temperature, the reaction wasquenched with 12 mL 1 M HCl and stirred vigorously for 30 min to fullycleave any aluminate complexes. The mixture was then diluted with EtOAc,extracted, washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product was purified by ISCO (80 g, 0-100%EtOAc/Hexanes, 33 min. SM peak recovered at 20%, Product peak) to affordIntermediate I-54 (213 mg, 0.739 mmol, 59.9% yield) as white powder.LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 287.8, 289.8 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.14 (s, 1H), 5.14 (d, J=6.4 Hz, 2H), 3.89 (s,3H), 3.42 (t, J=6.3 Hz, 1H), 2.33 (s, 3H).

Intermediate I-552-bromo-6-methoxy-5-methylbenzo[d]thiazole-4-carbaldehyde

To a solution of Intermediate I-54 (80 mg, 0.278 mmol) in DCE (2776 μl)was added manganese(IV) oxide (241 mg, 2.78 mmol). The solution washeated to reflux under an atmosphere of N₂ for 4 h. The reaction mixturewas allowed to cool to room temperature before being filtered overcelite and washed with EtOAc. The filtrate was concentrate in vacuo toafford Intermediate I-55 (61 mg, 0.213 mmol, 77% yield) as an off-whitesolid. This material was taken on without further purification. LC-MS:Method H, RT=1.04 min, MS (ESI) m/z: 285.7, 287.7 (M+H)⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 11.12 (s, 1H), 7.42 (s, 1H), 3.93 (s, 3H), 2.63 (s,3H).

Intermediate I-56 2-bromo-4-chloro-6-methoxy-5-methylbenzo[d]thiazole

Intermediate I-56A: 2-chloro-4-methoxy-3-methyl-1-nitrobenzene

This intermediate was prepared in a manner analogous to IntermediateI-43A. Thus 1-chloro-3-methoxy-2-methylbenzene was reacted to affordIntermediate I-56A (52% yield) as the major regioisomer isolated fromthe reaction mixture (second eluting on silica gel). LC-MS: Method H,RT=0.85 min, MS (ESI) m/z: None Observed (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.80 (d, J=8.8 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 3.93 (s,3H), 2.34 (s, 3H).

Intermediate I-56B: 2-chloro-4-methoxy-3-methylaniline

This intermediate was prepared in a manner analogous to IntermediateI-43B. Thus, Intermediate I-56A was reacted to afford Intermediate I-56B(42% yield) as a purple oil. LC-MS: Method H, RT=0.91 min, MS (ESI) m/z:172.1, 174.1 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.68-6.58 (m, 2H),3.77 (br. s., 2H), 3.76 (s, 3H), 2.27 (s, 3H).

Intermediate I-56C: 4-chloro-6-methoxy-5-methylbenzo[d]thiazol-2-amine

This intermediate was prepared in a manner analogous to IntermediateI-43C. Thus, Intermediate I-56B was reacted to afford Intermediate I-56C(81% yield) as a purple oil. LC-MS: Method H, RT=1.06 min, MS (ESI) m/z:229.1, 231.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (s, 1H), 7.34 (s,1H), 3.79 (s, 3H), 2.24 (s, 3H).

Intermediate I-56

This intermediate was prepared in a manner analogous to IntermediateI-43. Thus, Intermediate I-56C was reacted to afford Intermediate I-56(51% yield) as a beige solid. LC-MS: Method H, RT=1.36 min, MS (ESI)m/z: 292.0, 294.0, 295.9 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (s,1H), 7.34 (s, 1H), 3.79 (s, 3H), 2.24 (s, 3H).

Intermediate I-57 methyl2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)acetate

Intermediate I-57A: 2-amino-4-chloro-5-fluorobenzo[d]thiazol-6-ol,hydrobromide

A suspension of Intermediate I-43C (100 mg, 0.430 mmol) in acetic acid(2 mL) and HBr (48% in water) (2 mL, 17.68 mmol) was heated to 125° C.After 3 h of heating, the mixture was cooled to room temperature andconcentrated in vacuo to give Intermediate I-57A (116 mg, 0.387 mmol,90% yield) as its HBr salt. LC-MS: Method H, RT=0.80 min, MS (ESI) m/z:218.9, 220.8 (M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.36 (d, J=7.3 Hz,1H).

Intermediate I-57B: methyl2-((2-amino-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy) acetate

To a solution of Intermediate I-57A (129 mg, 0.431 mmol) in DMF (5 mL)was added Cs₂CO₃ (631 mg, 1.938 mmol) followed by methyl bromoacetate(0.044 mL, 0.474 mmol). The reaction mixture was stirred vigorously for30 min before being quenched with AcOH (0.247 mL, 4.31 mmol) followed by5 mL deionized water. This solution was diluted with DCM and extracted3×. The organic phase was concentrated and the crude residue waspurified by ISCO (40 g, 0-10% DCM/MeOH, 17 min. Product at 5%) to affordIntermediate I-57B (135 mg, 0.418 mmol, 97% yield). LC-MS: Method H,RT=0.90 min, MS (ESI) m/z: 290.8, 292.7 (M+H)⁺. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.33 (d, J=7.5 Hz, 1H), 4.77 (s, 2H), 3.78 (s, 3H).

Intermediate I-57C: methyl2-((2-amino-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy) acetate

This intermediate was prepared in a manner analogous to IntermediateI-43. Thus, Intermediate I-57B was reacted to afford Intermediate I-57C(57% yield) as a beige solid. LC-MS: Method H, RT=1.00 min, MS (ESI)m/z: 353.9, 356.0, 357.9 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.25(d, 1H-buried under CDCl₃), 4.77 (s, 2H), 3.82 (s, 3H).

Intermediate I-582-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)aceticacid

To a mixture of Intermediate I-57 (88 mg, 0.248 mmol) in THF (3.5 mL)and water (1.0 mL) was added LiOH monohydrate (51.2 mg, 1.241 mmol).After 30 min the reaction mixture was diluted with EtOAc and washed with1 M HCl. The organic phase was concentrated to afford Intermediate I-58(88 mg, 0.258 mmol, 104% yield) as a beige solid. This material wastaken forward without further purification. LC-MS: Method H, RT=0.88min, MS (ESI) m/z: 340.0, 342.0, 344.0 (M+H)⁺. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.62 (d, J=7.5 Hz, 1H), 4.83 (s, 2H).

Intermediate I-592-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)ethanol

This intermediate was prepared in a manner analogous to IntermediateI-51. Intermediate I-57 was reacted to afford Intermediate I-59 (77%yield) as a yellow solid. LC-MS: Method H, RT=1.07 min, MS (ESI) m/z:326.0, 327.9, 329.9 (M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.68 (d,J=7.3 Hz, 1H), 4.25-4.15 (m, 2H), 4.00-3.89 (m, 2H).

Intermediate I-60 2-bromo-5-fluorobenzo[d]thiazol-6-ol

A solution of Intermediate 277B (502 mg, 1.915 mmol) in CH₂Cl₂ (10 mL)was cooled to 0° C. To this mixture was slowly added BBr₃ (1 M inHexanes) (5.75 mL, 5.75 mmol) over 5 minutes. After this addition, thereaction mixture was allowed to thaw to room temperature overnight.After 16 h, the reaction mixture was poured into ice. The mixture wasdiluted with 30 mL of EtOAc and stirred vigorously for 10 min. Theorganic phase was separated and the aqueous phase was washed 2× withEtOAc. The combined organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to afford Intermediate I-60 (468 mg, 1.887 mmol,98% yield) as an off-white solid. LC-MS: Method H, RT=0.85 min, MS (ESI)m/z: 248.0, 249.9 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H),7.84 (d, J=11.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −135.05 (s, 1F).

Intermediate I-61 2((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)ethanol

Intermediate I-61A: methyl2-((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)acetate

This intermediate was prepared in a manner analogous to IntermediateI-52. Thus, Intermediate I-60 was reacted to afford Intermediate I-61A(96% yield) as a white solid. LC-MS: Method H, RT=0.92 min, MS (ESI)m/z: 320.1, 322.1 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.72 (d,J=11.0 Hz, 1H), 7.33 (d, J=7.7 Hz, 1H), 4.76 (s, 2H), 3.82 (s, 3H).

Intermediate I-61

This intermediate was prepared in a manner analogous to IntermediateI-51. Thus, Intermediate I-61A was reacted to afford Intermediate I-61(98% yield) as an off-white, amorphous solid. LC-MS: Method H, RT=0.81min, MS (ESI) m/z: 292.1, 294.1 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.70 (d, J=11.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 4.22-4.17 (m, 2H), 4.04(dt, J=6.2, 4.5 Hz, 2H), 2.10-2.04 (m, 1H).

Intermediate I-622-((2-bromo-5-fluoro-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl(6-fluoropyridin-3-yl) carbamate

To a solution of Intermediate I-53 (22 mg, 0.072 mmol) in THF (1.5 mL)was added DIEA (0.065 mL, 0.370 mmol) followed by a solution of phosgene(15% by wt. in toluene) (0.253 mL, 0.359 mmol) at room temperature.After 2 h of stirring, the crude chlorofomate intermediate wasconcentrated to remove excess phosgene and retaken in THF (1 mL).Another batch of DIEA (0.065 mL, 0.370 mmol) was added followed by6-fluoropyridin-3-amine (24.90 mg, 0.222 mmol). After 15 min, the crudereaction mixture was concentrated and purified by ISCO (12 g, 0-70%EtOAc/Hexanes, 16 min. Product at 35%) to afford Intermediate I-62 (28mg, 0.070 mmol, 95% yield) as an off-white solid. LC-MS: Method H,RT=1.21 min, MS (ESI) m/z: 443.1, 445.2 (M+H)⁺. ¹H NMR (400 MHz, THF) δ9.10 (br. s., 1H), 8.07 (br. s., 1H), 8.02-7.91 (m, 1H), 7.40 (t, J=7.7Hz, 1H), 6.80 (dd, J=8.8, 3.5 Hz, 1H), 4.46-4.38 (m, 2H), 4.26-4.18 (m,2H), 2.44 (dd, J=3.6, 2.5 Hz, 3H).

Intermediate I-632((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)ethyl(6-fluoropyridin-3-yl)carbamate

This intermediate was prepared in a manner analogous to IntermediateI-62. Thus, Intermediate I-59 was reacted to afford Intermediate I-63(90% yield) as an off-white solid. LC-MS: Method H, RT=1.18 min, MS(ESI) m/z: 464.0, 466.0, 468.0 (M+H)⁺. ¹H NMR (400 MHz, THF) δ 9.22 (br.s., 1H), 8.19 (br. s., 1H), 8.12-8.02 (m, 1H), 7.70 (d, J=7.3 Hz, 1H),6.92 (dd, J=8.8, 3.5 Hz, 1H), 4.56-4.53 (m, 2H), 4.41-4.37 (m, 2H).

Intermediate I-645-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol

Intermediate I-64A:2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-ol

A microwave vial was charged with Intermediate I-1 (106 mg, 0.314 mmol),Intermediate I-60 (65 mg, 0.262 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (17.12 mg, 0.021 mmol). A solvent mixture oftoluene (1638 μl), EtOH (546 μl) and 2.0 M Na₂CO₃ (197 μl, 0.393 mmol)was then added, and the resulting solution was sparged with argon for 10min before being sealed and then heated in the microwave at 130° C. for30 min. The crude reaction mixture was diluted with EtOAc and filteredover celite before being concentrated and purified by ISCO (24 g, 0-100%EtOAc/Hexanes, 16 min. Product at 35%.) to afford Intermediate I-64A (95mg, 0.252 mmol, 96% yield) as a dark yellow solid. LC-MS: Method H,RT=1.06 min, MS (ESI) m/z: 378.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d)δ 8.76 (d, J=2.0 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J=10.8 Hz, 1H), 7.80(s, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 5.30 (d, J=5.1Hz, 1H), 2.68 (s, 3H).

Intermediate I-64

To a solution of Intermediate I-64A (20 mg, 0.053 mmol) in THF (1 mL)was added a 0.5 M NaOMe solution in MeOH (0.530 mL, 0.265 mmol). After 1h, the reaction mixture was diluted with EtOAc and quenched with 1.0 NHCl. The organic phase was extracted, dried over MgSO₄, filtered andconcentrated in vacuo to afford Intermediate I-64 (18 mg, 0.053 mmol,99% yield) as a yellow solid. This material was taken on without furtherpurification. LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 342.2 (M+H)⁺.¹H NMR (400 MHz, THF) δ 8.95 (br. s., 1H), 8.70 (d, J=1.3 Hz, 1H), 8.54(s, 1H), 7.80-7.67 (m, 2H), 7.46 (d, J=8.6 Hz, 1H), 4.10 (s, 3H), 2.63(s, 3H).

Intermediate I-654-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol

Intermediate I-65A4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-ol

This intermediate was prepared in a manner analogous to IntermediateI-64A. Thus, Intermediate I-1 was reacted with Intermediate I-44 toafford Intermediate I-65A (81% yield) as a bright yellow solid. LC-MS:Method H, RT=1.15 min, MS (ESI) m/z: 412.0, 414.1 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.94-9.01 (m, 1H), 8.69-8.78 (m, 1H), 7.72-8.10 (m, 2H),7.64-7.70 (m, 1H), 2.70 (s, 3H).

Intermediate I-65

This intermediate was prepared in a manner analogous to IntermediateI-64. Thus, Intermediate I-65A was reacted to afford Intermediate I-65(100% yield) as a dark orange solid. LC-MS: Method H, RT=1.36 min, MS(ESI) m/z: 376.0, 378.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.94-9.01(m, 1H), 8.69-8.78 (m, 1H), 7.72-8.10 (m, 2H), 7.64-7.70 (m, 1H), 2.70(s, 3H).

Intermediate I-662-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanol

Intermediate I-66A:2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)ethanol

This intermediate was prepared in a manner analogous to IntermediateI-64A. Thus, Intermediate I-1 was reacted with Intermediate I-61 toafford Intermediate I-66A (75% yield) as a yellow solid. LC-MS: MethodH, RT=1.07 min, MS (ESI) m/z: 422.2 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.76 (d, J=1.8 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J=11.4Hz, 1H), 7.80 (dd, J=1.8, 0.9 Hz, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.50 (d,J=7.7 Hz, 1H), 4.29-4.23 (m, 2H), 4.10-4.03 (m, 2H), 2.69 (s, 3H), 2.14(t, J=6.4 Hz, 1H).

Intermediate I-66

This intermediate was prepared in a manner analogous to IntermediateI-64. Intermediate I-66A was reacted to afford Intermediate I-66 (43%yield) as a dark orange solid. LC-MS: Method H, RT=1.08 min, MS (ESI)m/z: 386.1 (M+H)⁺. ¹H NMR (400 MHz, THF) δ 8.71 (d, J=1.8 Hz, 1H), 8.55(s, 1H), 7.77-7.73 (m, 2H), 7.71 (d, J=8.1 Hz, 1H), 4.22-4.16 (m, 2H),4.10 (s, 3H), 3.93-3.85 (m, 2H), 2.64 (s, 3H).

Intermediate I-67(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol

To a suspension of Intermediate I-64 (30 mg, 0.088 mmol) neat in(R)-2-methyloxirane (1 mL, 14.29 mmol) was added tetrabutylammoniumbromide (56.7 mg, 0.176 mmol) followed by K₂CO₃ (36.4 mg, 0.264 mmol).The reaction vessel was sealed, heated to 65° C. and stirred vigorouslyfor 4 h. The reaction mixture was then cooled to room temperature andquenched with a few drops of AcOH. The resulting mixture wasconcentrated and purified by ISCO (12 g, 0-70% EtOAc/Hexanes, 16 min.Product at 38%) to afford Intermediate I-67 (27 mg, 0.068 mmol, 77%yield) as a bright yellow solid. LC-MS: Method H, RT=1.16 min, MS (ESI)m/z: 400.1 (M+H)⁺. ¹H NMR (400 MHz, THF) δ 8.70 (d, J=1.8 Hz, 1H), 8.56(s, 1H), 7.78-7.73 (m, 2H), 7.71 (d, J=8.1 Hz, 1H), 4.10 (s, 3H),4.16-4.07 (m, 1H), 4.07-4.00 (m, 1H), 4.00-3.92 (m, 1H), 2.64 (s, 3H),2.55 (br. s, 1H), 1.26 (d, J=6.4 Hz, 3H).

Intermediate I-68(S)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol

This intermediate was prepared in a manner analogous to IntermediateI-67. Intermediate I-64 was reacted with (S)-2-methyloxirane to affordIntermediate I-68 (73% yield) as a bright yellow solid. LC-MS: Method H,RT=1.07 min, MS (ESI) m/z: 422.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d)δ 8.76 (d, J=1.8 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J=11.4 Hz, 1H), 7.80(dd, J=1.8, 0.9 Hz, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.50 (d, J=7.7 Hz,1H), 4.29-4.23 (m, 2H), 4.10-4.03 (m, 2H), 2.69 (s, 3H), 2.14 (t, J=6.4Hz, 1H).

Intermediate I-69(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol

This intermediate was prepared in a manner analogous to IntermediateI-67. Thus, Intermediate I-65 was reacted with (R)-2-methyloxirane toafford Intermediate I-69 (74% yield) as a bright yellow solid. LC-MS:Method H, RT=1.20 min, MS (ESI) m/z: 434.1 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.78 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.01 (d, J=7.7 Hz, 1H),7.88 (s, 1H), 5.00 (d, J=4.2 Hz, 1H), 4.10 (s, 3H), 4.10-4.00 (m, 3H),2.67 (s, 3H), 1.22 (d, J=5.9 Hz, 3H).

Intermediate I-70(S)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-1-ol

Intermediate I-70A:(S)-6-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole

A solution of Intermediate I-64 (30 mg, 0.088 mmol) andtriphenylphosphine (92 mg, 0.352 mmol) in THF (1.0 mL) was heated to 65°C. To this mixture was added a solution of(R)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (84 mg, 0.439 mmol)mixed with DIAD (0.085 mL, 0.439 mmol) in THF (1.0 mL) dropwise over 1 hvia syringe pump. At the end of addition, the crude mixture was allowedto cool to room temperature then was concentrated and purified by ISCO(12 g, 0-10% EtOAc/Hexanes, 16 min. Product at 7%) to affordIntermediate I-70A (31 mg, 0.060 mmol, 68.7% yield) as a yellow oil.LC-MS: Method H, RT=1.56 min, MS (ESI) m/z: 514.3 (M+H)⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.61 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 7.80 (d,J=11.2 Hz, 1H), 7.75 (d, J=0.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 4.52(sxt, J=5.9 Hz, 1H), 4.13 (s, 3H), 3.89 (dd, J=10.7, 5.8 Hz, 1H), 3.75(dd, J=10.7, 5.0 Hz, 1H), 2.65 (s, 3H), 1.39 (d, J=6.2 Hz, 3H), 0.89 (s,9H), 0.09 (s, 3H), 0.06 (s, 3H).

Intermediate I-70

To a solution of Intermediate I-70A (20 mg, 0.039 mmol) in THF (0.8 mL)and methanol (0.2 mL) was added several drops of concentrated HCl(12.1M, 0.016 mL, 0.195 mmol). After stirring for 5 min at roomtemperature, the reaction mixture was quenched with saturated NaHCO₃.This solution was then diluted with DCM and extracted. The organic phasewas dried over MgSO₄, filtered and concentrated in vacuo to affordIntermediate I-70 (15 mg, 0.039 mmol, 100% yield), which was taken onwithout further purification. LC-MS(ESI) m/z: 400.2 (M+H)⁺. RT=1.11 min(1 min gradient, ACN/water/TFA). ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s,1H), 8.57 (d, J=1.7 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.94 (d, J=11.6 Hz,1H), 7.82 (d, J=0.8 Hz, 1H), 4.96 (t, J=5.6 Hz, 1H), 4.63-4.55 (m, 1H),4.08 (s, 3H), 3.68-3.61 (m, 1H), 3.61-3.55 (m, 1H), 2.63 (s, 3H), 2.51(dt, J=3.5, 1.7 Hz, 8H), 1.30 (d, J=6.1 Hz, 3H).

Intermediate I-71(R)-2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-1-ol

Intermediate I-71A:(R)-6-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole

This intermediate was prepared in a manner analogous to IntermediateI-70A. Intermediate I-64 was reacted with(S)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol to afford IntermediateI-71A (61% yield) as a yellow oil. LC-MS: Method H, RT=1.56 min, MS(ESI) m/z: 514.3 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.61 (d, J=2.0Hz, 1H), 8.55 (s, 1H), 7.80 (d, J=11.2 Hz, 1H), 7.75 (d, J=0.7 Hz, 1H),7.56 (d, J=7.7 Hz, 1H), 4.52 (sxt, J=5.9 Hz, 1H), 4.13 (s, 3H), 3.89(dd, J=10.7, 5.8 Hz, 1H), 3.75 (dd, J=10.7, 5.0 Hz, 1H), 2.65 (s, 3H),1.39 (d, J=6.2 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H).

Intermediate I-71

This intermediate was prepared in a manner analogous to IntermediateI-70. Thus, Intermediate I-71A was reacted to afford Intermediate I-71(94% yield). LC-MS(ESI) m/z: 400.2 (M+H)⁺. RT=1.11 min (1 min gradient,ACN/water/TFA). ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.57 (d, J=1.7Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.94 (d, J=11.6 Hz, 1H), 7.82 (d, J=0.8Hz, 1H), 4.96 (t, J=5.6 Hz, 1H), 4.63-4.55 (m, 1H), 4.08 (s, 3H),3.68-3.61 (m, 1H), 3.61-3.55 (m, 1H), 2.63 (s, 3H), 2.51 (dt, J=3.5, 1.7Hz, 8H), 1.30 (d, J=6.1 Hz, 3H).

Intermediate I-72(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ol

Intermediate I-72A:(2R,3S)-3((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol

To a solution of Intermediate I-60 (1.0 g, 4.03 mmol) in THF (26.9 ml)was added (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (0.736 g,4.84 mmol) followed by potassium carbonate (0.669 g, 4.84 mmol). Thereaction mixture was sealed and heated to 65° C. for 16 h. The reactionmixture was cooled to 0° C. and concentrated sulfuric acid (0.430 ml,8.06 mmol) was added (caution: significant bubbling observed) followedby water (0.218 ml, 12.09 mmol). The reaction mixture was allowed tothaw to room temperature for 10 min before being quenched with 1.5 MK₂HPO₄, extracted with EtOAc, washed with brine, dried over MgSO₄,filtered over celite and concentrated down to afford Intermediate I-72A(1.29 g, 4.03 mmol) as beige solid. The crude material was taken onwithout further purification. LC-MS: Method H, RT=0.96 min, MS (ESI)m/z: 319.9, 321.9 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (d, J=8.1 Hz,1H), 7.89 (d, J=11.4 Hz, 1H), 4.86 (d, J=5.3 Hz, 1H), 4.35-4.25 (m, 1H),3.84-3.73 (m, 1H), 1.26 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.4 Hz, 3H). ¹⁹FNMR (376 MHz, DMSO-d₆) δ −132.96.

Intermediate I-72B(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol

To a 250 mL round bottom flask charged with Intermediate I-1 (787 mg,2.342 mmol) and Intermediate I-72A (750 mg, 2.342 mmol) was addedtoluene (8784 μl) and EtOH (2928 μl) followed by a 2M solution of sodiumcarbonate (1757 μl, 3.51 mmol). The mixture was stirred vigorously andsparged with argon for 10 minutes.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (191 mg, 0.234 mmol) was then added and themixture was sparged with argon for an additional 5 min. The reactionmixture was heated to reflux under an atmosphere of argon. After 2 h ofheating, the reaction mixture was diluted with EtOAc and filteredthrough celite before being concentrated, dry loaded onto celite andpurified by ISCO (120 g, 0-100% DCM/EtOAc, Product at 25%) to affordIntermediate I-72B (470 mg, 1.046 mmol, 44.6% yield) as a bright yellowsolid. LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 450.9 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.76 (d, J=2.0 Hz, 1H), 8.69 (s, 1H), 7.83 (d,J=11.4 Hz, 1H), 7.80 (dd, J=1.9, 1.0 Hz, 1H), 7.66 (t, J=71.8 Hz, 1H),7.54 (d, J=7.7 Hz, 1H), 4.40 (qd, J=6.3, 3.3 Hz, 1H), 4.18-4.06 (m, 1H),2.69 (s, 3H), 2.14 (d, J=4.8 Hz, 1H), 1.38 (d, J=6.4 Hz, 3H), 1.30 (d,J=6.6 Hz, 3H). ¹⁹F NMR (376 MHz, CHLOROFORM-d) δ −89.77, −132.68.

Intermediate I-72

Intermediate I-72B (470 mg, 1.046 mmol) was co-evaporated with tolueneto removed adventitious water. The crude solid was retake in THF (20.900mL) and a 0.5 M solution sodium methoxide in MeOH (20.91 mL, 10.46 mmol)was added causing the solution to turn dark red. The reaction mixturewas quenched after 30 min with 1.0 N HCl (21 mL) causing the solution toreturn to a bright yellow color. The reaction mixture was diluted with150 mL EtOAc, extracted and washed with brine. The organic phase wasdried over MgSO₄, filtered over a pad of SiO₂ gel and concentrated toafford Intermediate I-72 (430 mg, 1.040 mmol, 99% yield) as a yellowsolid. LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 414.0 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.62 (d, J=1.8 Hz, 1H), 8.55 (s, 1H), 7.83 (d,J=11.2 Hz, 1H), 7.77 (d, J=0.9 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H),4.43-4.34 (m, 1H), 4.13 (s, 3H), 2.65 (s, 3H), 2.15 (d, J=4.8 Hz, 1H),1.37 (d, J=6.2 Hz, 3H), 1.29 (d, J=6.6 Hz, 3H). ¹⁹F NMR (376 MHz,CHLOROFORM-d) δ −133.04.

Intermediate I-73(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

To a solution of Intermediate I-72B (170 mg, 0.332 mmol) in THF (6.5 mL)was added a 15% phosgene solution in toluene (2354 μl, 3.34 mmol). Theresulting slurry was allowed to stir at room temperature for 16 h beforebeing concentrated down to the crude chloroformate intermediate. Thiscrude residue was retaken in THF (6.5 mL) and 2-methylpyrimidin-5-amine(39.9 mg, 0.365 mmol) followed by pyridine (0.134 mL, 1.660 mmol) wereadded to the reaction mixture. After 10 min, the reaction mixture wasconcentrated and purified by ISCO (40 g, 0-100% EtOAc/Hex, Product at85%) to afford Intermediate I-73 (182 mg, 0.311 mmol, 94% yield) as ayellow solid. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 585.2 (M+H)⁺.¹H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (d, J=2.0 Hz, 1H), 8.72 (br. s.,2H), 8.69 (s, 1H), 7.86-7.78 (m, 2H), 7.66 (t, J=71.8 Hz, 1H), 7.53 (d,J=7.9 Hz, 1H), 6.49 (br. s., 1H), 5.21-5.12 (m, 1H), 4.63 (dd, J=6.4,3.3 Hz, 1H), 2.69 (s, 3H), 2.68 (s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.44(d, J=6.4 Hz, 3H). ¹⁹F NMR (376 MHz, CHLOROFORM-d) δ −89.78 (s, 3F),−132.17 (s, 1F)

Intermediate I-74 Methyl5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate

To a solution of Intermediate I-72 (30 mg, 0.073 mmol) in THF (1.5 mL)was added a 15% phosgene solution in toluene (512 μl, 0.726 mmol). Theresulting slurry was allowed to stir at room temperature for 16 h beforebeing concentrated down to the crude chloroformate intermediate. Thiscrude residue was retaken in THF (1.5 mL) and methyl 5-aminopicolinate(13.25 mg, 0.087 mmol) was added followed by pyridine (0.059 mL, 0.726mmol). After 10 min, the reaction mixture was concentrated and loadeddirectly onto an ISCO column (12 g, 0-60%, DCM/EtOAc, Product at 28%) toafford Intermediate I-74 (40 mg, 0.068 mmol, 93% yield) as a lightyellow solid. LC-MS: Method H, RT=1.26 min, MS (ESI) m/z: 592.1 (M+H)⁺.¹H NMR (400 MHz, CHLOROFORM-d) δ 8.64-8.59 (m, 1H), 8.57 (d, J=1.8 Hz,1H), 8.55 (d, J=2.6 Hz, 1H), 8.51 (s, 1H), 8.18-8.11 (m, 1H), 8.10-8.06(m, 1H), 7.79 (d, J=11.2 Hz, 1H), 7.74 (d, J=0.9 Hz, 1H), 7.50 (d, J=7.7Hz, 1H), 7.18 (s, 1H), 5.16 (qd, J=6.5, 3.1 Hz, 1H), 4.65-4.57 (m, 1H),4.12 (s, 3H), 3.95 (s, 3H), 2.63 (s, 3H), 1.46 (d, J=6.6 Hz, 3H), 1.42(d, J=6.4 Hz, 3H).

Intermediate I-75 Methyl5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate

Intermediate I-75A: (ethyl5-(5-fluoro-6-(((2S,3R)-3-hydroxybutan-2-yl)oxy)benzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate

This intermediate was prepared in a manner analogous to IntermediateI-70A. Thus, Intermediate I-72A was reacted with Intermediate I-15 andpurified by ISCO (0-100% EtOAc/Hex, Product at 60%) to affordIntermediate I-75A (79% yield) as a dark yellow solid. LC-MS: Method H,RT=1.17 min, MS (ESI) m/z: 456.1 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d)δ 9.62 (s, 1H), 8.99 (d, J=2.0 Hz, 1H), 8.20 (s, 1H), 7.84 (d, J=11.2Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 4.67-4.58 (m, 2H), 4.47-4.36 (m, 1H),4.17-4.08 (m, 1H), 2.74 (s, 3H), 2.14 (d, J=4.6 Hz, 1H), 1.56-1.53 (m,3H), 1.38 (d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H).

Intermediate I-75

This intermediate was prepared in a manner analogous to IntermediateI-73. Thus Intermediate I-75A was reacted to afford Intermediate I-75(50% yield) as a yellow solid. LC-MS: Method H, RT=1.08 min, MS (ESI)m/z: 591.8 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.97 (br. s., 1H), 9.46(s, 1H), 8.85 (br. s., 1H), 8.73 (br. s., 2H), 8.18 (br. s., 1H), 8.05(d, J=7.6 Hz, 1H), 7.94 (d, J=11.6 Hz, 1H), 5.12 (br. s., 1H), 4.84 (br.s., 1H), 4.49 (d, J=6.7 Hz, 2H), 2.69 (br. s., 3H), 2.56 (s, 3H),1.56-1.34 (m, 9H).

Intermediate I-76(2R,3S)-3((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol

Intermediate I-76A: (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2-oxide

To a solution of thionyl chloride (5.37 ml, 73.5 mmol) in DCM (235 ml)was added (2R,3R)-butane-2,3iol (5.37 ml, 58.8 mmol). The reactionmixture immediately became opaque and bubbled. Over time, the solutionbecame clear once again. After 30 min, the reaction mixture wascarefully concentrated [Note: This product is volatile]. IntermediateI-76A (8.01 g, 58.8 mmol, 100% yield) was isolated as a light tan oilmixed with some residual DCM. The product was taken on to the subsequentsulfur oxidation without purification. ¹H NMR (400 MHz, CDCl₃) δ 4.68(dq, J=9.0, 6.2 Hz, 1H), 4.11 (dq, J=8.9, 6.3 Hz, 1H), 1.57 (d, J=6.2Hz, 3H), 1.48 (d, J=6.2 Hz, 3H).

Intermediate I-76B: (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide

A solution of Intermediate I-76A in CCl₄ (73.4 ml), acetonitrile (73.4ml) and H₂O (147 ml) was cooled to 0° C. Sodium periodate (18.85 g, 88mmol) was added to the mixture followed by ruthenium(III) chloride(0.244 g, 1.175 mmol). The resulting mixture was stirred at 0° C. for 1h, over which time it took on a reddish-brown hue. The reaction mixturewas then diluted with 200 mL DI H₂O and extracted with 500 mL EtOAc. Theorganic phase was washed with brine, dried over MgSO₄, and filtered overa pad of silica gel. This organic solution was concentrated down to ablack oil and retaken in DCM. This DCM solution was filtered over asecond pad of silica gel which removed more of the ruthenium impurities.The resulting solution was concentrated to afford Intermediate I-76B(7.6 g, 49.9 mmol, 85% yield) as a brown tinged oil. [Note: Thismaterial can be stored as a frozen solid at −20° C.]. ¹H NMR (400 MHz,CHLOROFORM-d) δ 4.75-4.63 (m, 2H), 1.58-1.52 (m, 6H).

Intermediate I-76

To a solution of Intermediate I-60 (2.65 g, 10.68 mmol) in THF (42.7 ml)was added Intermediate I-76B followed by potassium carbonate (2.215 g,16.02 mmol). A reflux condenser was attached, and the reaction mixturewas heated to reflux (65° C.) overnight. After 15 h of refluxing, thesolution was cooled to 0° C. Cleavage of the resulting sulfateintermediate was affected by the addition of concentrated sulfuric acid(1.708 ml, 32.0 mmol) followed by water (0.962 ml, 53.4 mmol) [Note:vigorous bubbling observed]. The reaction mixture was allowed to thaw toroom temperature and stirred vigorously for 1 h. The reaction mixturewas then quenched with 100 mL of a 1.5 M K₂HPO₄ solution, extracted with300 mL EtOAc, washed with brine, dried over MgSO₄, filtered andconcentrated to afford a beige solid. This solid was dry loaded ontoCelite and purified by ISCO (220 g, 0-50% EtOAc/DCM, 36 min. Product at15%) to afford Intermediate I-76 (3.1 g, 9.68 mmol, 91% yield, 99% ee)as an off-white solid. LC-MS: Method H, RT=0.78 min, MS (ESI) m/z:399.9, 401.9 (M+H)⁺-Sulfate Intermediate. LC-MS: Method H, RT=0.93 min,MS (ESI) m/z: 320.0, 322.0 (M+H)⁺-Desired Alcohol. Chiral HPLC: ChiralAD 10 micron 4.6×250 mm, Solvent A (heptane), Solvent B (1:1 MeOH/EtOH).Isocratic gradient at 16% B, product retention time 6.0 min. ¹H NMR (400MHz, DMSO-d₆) δ 7.98 (d, J=8.4 Hz, 1H), 7.91 (d, J=11.7 Hz, 1H), 4.90(d, J=5.3 Hz, 1H), 4.35-4.26 (m, 1H), 3.85-3.73 (m, 1H), 1.27 (d, J=6.2Hz, 3H), 1.16 (d, J=6.4 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −132.96(s, 1F).

Intermediate I-77(2R,3S)-3-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol

This intermediate was prepared in a manner analogous to IntermediateI-76. Thus, Intermediate I-44 was reacted with Intermediate I-76A toafford Intermediate I-77 (58% yield) as an off-white solid. LC-MS:Method H, RT=1.00 min, MS (ESI) m/z: 353.9, 355.9, 358.0 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.34 (d, J=7.0 Hz, 1H), 4.38 (dd, J=6.3, 3.4 Hz, 1H),4.16-4.03 (m, 1H), 2.01 (d, J=4.8 Hz, 1H), 1.37 (d, J=6.4 Hz, 3H), 1.31(d, J=6.6 Hz, 3H).

Intermediate I-78(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol

To a flask charged with Intermediate I-1 (254 mg, 0.756 mmol) andIntermediate I-76 (220 mg, 0.687 mmol) was added toluene (2577 μl) andEtOH (859 μl) followed by a 2 M aqueous solution of sodium carbonate(515 μl, 1.031 mmol). The mixture was stirred vigorously and spargedwith argon for 10 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1)(56.1 mg, 0.069 mmol) was then added and the mixture was sparged withargon for an additional 5 min. The flask was then heated to reflux underan atmosphere of argon. After 2 h of refluxing, the reaction mixture wasdiluted with EtOAc, filtered over Celite and concentrated. The cruderesidue was dry-loaded onto Celite and purified by ISCO (80 g, 0-70%DCM/EtOAc, product at 20%) to afford Intermediate I-78 (260 mg, 0.578mmol, 84% yield) as a bright yellow foaming solid. LC-MS: Method H,RT=1.14 min, MS (ESI) m/z: 450.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.76(d, J=2.0 Hz, 1H), 8.69 (s, 1H), 7.83 (d, J=11.4 Hz, 1H), 7.80 (dd,J=1.9, 1.0 Hz, 1H), 7.66 (t, J=71.8 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H),4.40 (qd, J=6.3, 3.3 Hz, 1H), 4.18-4.06 (m, 1H), 2.69 (s, 3H), 2.14 (d,J=4.8 Hz, 1H), 1.38 (d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H). ¹⁹F NMR(376 MHz, CDCl₃) δ −89.77 (s, 2F), −132.68 (s, 1F).

Intermediate I-79(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ol

The starting material Intermediate I-78 (0.91 g, 2.025 mmol) wasco-evaporated with toluene to remove any adventitious water. The driedsolid was retaken in THF (40.5 ml) and a 0.5 M solution of sodiummethoxide in methanol (40.5 ml, 20.25 mmol) was added. After 1 h ofstirring, the reaction mixture was quenched with 1.0 N HCl (41 mL). Themixture was then diluted with 500 mL EtOAc and washed with 150 mL Brine.The organic phase was dried over MgSO₄, filtered, and concentrated ontoCelite for dry-load purification by ISCO (80 g, 0-100% DCM/EtOAc) togive Intermediate I-79 (0.73 g, 1.766 mmol, 87% yield) as a yellow foamysolid. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 414.1 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.58 (d, J=1.8 Hz, 1H), 7.99 (d,J=8.4 Hz, 1H), 7.95 (d, J=11.7 Hz, 1H), 7.83 (d, J=0.7 Hz, 1H), 4.91 (d,J=5.1 Hz, 1H), 4.38 (quin, J=5.8 Hz, 1H), 4.09 (s, 3H), 3.87-3.77 (m,1H), 2.63 (s, 3H), 1.31 (d, J=6.2 Hz, 3H), 1.19 (d, J=6.2 Hz, 3H)

Intermediate I-80(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol

To a solution of Intermediate I-78 (370 mg, 0.823 mmol) in THF (6174 μl)was added ethanol (2058 μl) followed by the portion-wise addition ofsodium hydride (329 mg, 8.23 mmol). After 10 minutes of stirring, thereaction mixture was quenched with saturated NH₄Cl (˜2 mL), and theresulting mixture was concentrated onto Celite for dry loading andpurified by ISCO (80 g, 0-70% DCM/EtOAc, 33 min, product at 20%) toafford Intermediate I-80 (320 mg, 0.749 mmol, 91% yield) as a brightyellow solid. LC-MS: Method H, RT=1.48 min, MS (ESI) m/z: 428.1 (M+H)⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 7.99(d, J=8.1 Hz, 1H), 7.95 (d, J=11.7 Hz, 1H), 7.81 (s, 1H), 4.91 (d, J=5.3Hz, 1H), 4.54 (q, J=7.0 Hz, 2H), 4.37 (quin, J=5.8 Hz, 1H), 3.87-3.78(m, 1H), 2.63 (s, 3H), 1.45 (t, J=7.0 Hz, 3H), 1.31 (d, J=6.2 Hz, 3H),1.19 (d, J=6.4 Hz, 3H).

Intermediate I-81(2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ol

This intermediate was prepared in a manner analogous to IntermediateI-78. Thus, Intermediate I-9 was reacted with Intermediate I-77 toafford Intermediate I-81 (25% yield) as a yellow solid. LC-MS: Method H,RT=1.29 min, MS (ESI) m/z: 447.9, 449.8 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 8.71 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.41 (d,J=7.0 Hz, 1H), 4.43-4.33 (m, 1H), 4.15-4.06 (m, 4H), 2.65 (s, 3H), 2.15(d, J=4.2 Hz, 1H), 1.37 (d, J=6.4 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H).

Intermediate I-82 (R)-methyl5-((((1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate

To a solution Intermediate I-67 (194 mg, 0.486 mmol) in THF (9714 μl)was added a 15% phosgene solution in toluene (3425 μl, 4.86 mmol). Theresulting slurry was allowed to stir overnight before being concentrateddown to a crude yellow residue. This intermediate chloroformate wasretaken in THF (9714 μl) and added dropwise to a premixed solution ofmethyl 5-aminopicolinate (217 mg, 1.429 mmol) and pyridine (385 μl, 4.76mmol) in THF (9526 μl). After 10 min of stirring, the reaction mixturewas concentrated and loaded directly onto an ISCO cartridge forpurification (40 g, 0-100% EtOAc/DCM, product at 35%) to affordIntermediate I-82 (250 mg, 0.433 mmol, 91% yield) as a yellow solid.LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 578.2 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.40 (s, 1H), 8.78-8.72 (m, 2H), 8.58 (d, J=1.8 Hz,1H), 8.12-7.94 (m, 4H), 7.84 (s, 1H), 5.30 (td, J=6.2, 3.2 Hz, 1H),4.47-4.36 (m, 1H), 4.35-4.24 (m, 1H), 4.09 (s, 3H), 3.84 (s, 3H), 2.64(s, 3H), 1.45 (d, J=6.6 Hz, 3H).

Intermediate I-83 (R)-methyl4-((((1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate

This intermediate was prepared in a manner analogous to IntermediateI-82. Thus, Intermediate I-67 was reacted with methyl 4-aminopicolinateto afford Intermediate I-83 (59% yield) as a yellow solid. LC-MS: MethodH, RT=1.33 min, MS (ESI) m/z: 578.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.63-8.57 (m, 2H), 8.53 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.81 (d, J=11.4Hz, 1H), 7.78-7.70 (m, 2H), 7.47 (d, J=7.7 Hz, 1H), 7.14 (s, 1H),5.43-5.33 (m, 1H), 4.30-4.17 (m, 2H), 4.12 (s, 3H), 3.98 (s, 3H), 2.64(s, 3H), 1.51 (d, J=6.4 Hz, 3H).

Intermediate I-84 (R)-methyl5-((((1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate

This intermediate was prepared in a manner analogous to IntermediateI-82. Thus, Intermediate I-67 was reacted with Intermediate I-107 toafford Intermediate I-84 (66% yield) as a yellow solid. LC-MS: Method H,RT=1.14 min, MS (ESI) m/z: 579.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ10.57 (br. s., 1H), 9.01 (s, 2H), 8.76 (s, 1H), 8.59 (d, J=2.0 Hz, 1H),8.03 (d, J=8.4 Hz, 1H), 7.99 (d, J=11.7 Hz, 1H), 7.85 (dd, 1.0 Hz, 1H),5.31 (td, J=6.2, 3.2 Hz, 1H), 4.45-4.38 (m, 1H), 4.35-4.27 (m, 1H), 4.10(s, 3H), 3.87 (s, 3H), 2.64 (s, 3H), 1.45 (d, J=6.6 Hz, 3H)

Intermediate I-85 Methyl4-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate

This intermediate was prepared in a manner analogous to IntermediateI-82. Thus, Intermediate I-79 was reacted with methyl 4-aminopicolinateto afford Intermediate I-85 (46% yield) as a yellow solid. LC-MS: MethodH, RT=1.10 min, MS (ESI) m/z: 592.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.58 (d, J=1.8 Hz, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.51 (s, 1H), 7.99 (d,J=2.0 Hz, 1H), 7.80 (d, J=11.4 Hz, 1H), 7.75 (d, J=0.9 Hz, 1H), 7.69(dd, J=5.6, 2.1 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.12 (s, 1H), 5.16 (qd,J=6.5, 3.0 Hz, 1H), 4.67-4.56 (m, 1H), 4.12 (s, 3H), 3.95 (s, 3H), 2.64(s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.43 (d, J=6.4 Hz, 3H).

Intermediate I-86 Methyl5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate

This intermediate was prepared in a manner analogous to IntermediateI-82. Thus, Intermediate I-67 was reacted with Intermediate I-107 toafford Intermediate I-86 (66% yield) as a yellow solid. LC-MS: Method H,RT=1.19 min, MS (ESI) m/z: 593.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.03(s, 2H), 8.62 (br. s., 1H), 8.57 (d, J=1.8 Hz, 1H), 8.51 (s, 1H), 7.78(d, J=11.4 Hz, 1H), 7.76-7.73 (m, 1H), 7.49 (d, J=7.7 Hz, 1H), 5.17 (qd,J=6.5, 3.1 Hz, 1H), 4.62 (qd, J=6.4, 2.9 Hz, 1H), 4.12 (s, 3H), 4.02 (s,3H), 2.64 (s, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H).

Intermediate I-87 (R)-methyl4-((((1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl)oxy)carbonyl)amino)picolinate

This intermediate was prepared in a manner analogous to IntermediateI-82. Thus, Intermediate I-69 was reacted with methyl 4-aminopicolinateto afford Intermediate I-87 (58% yield) as a yellow solid. LC-MS: MethodH, RT=1.12 min, MS (ESI) m/z: 612.2, 614.1 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.76 (d, J=1.5 Hz, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.55 (s, 1H),8.04 (d, J=2.0 Hz, 1H), 7.80 (dd, J=2.0, 0.9 Hz, 1H), 7.75 (dd, 2.2 Hz,1H), 7.43 (d, J=7.3 Hz, 1H), 7.01 (s, 1H), 5.46-5.35 (m, 1H), 4.35-4.20(m, 2H), 4.16 (s, 3H), 4.02 (s, 3H), 2.69 (s, 3H), 1.55 (d, J=6.6 Hz,3H).

Intermediate I-88(2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate

Intermediate I-88A:(2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ylcarbonochloridate

To a solution Intermediate I-72A (780 mg, 2.436 mmol) in THF (24.4 mL,0.1 M) was added 15% phosgene in toluene (8.59 mL, 12.18 mmol). Theresulting slurry was allowed to stir at room temperature. After t=5 h,the resulting mixture was concentrated to remove the excess phosgene andafford Intermediate I-88A (824 mg, 2.436 mmol) as a yellow solid.Quantitative yield was assumed, and this material was telescope into thenext reaction without purification. LC-MS: Method H, RT=1.14 min, MS(ESI) m/z: 338.0, 339.9 (M+H)⁺.

Intermediate I-88B:(2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-yl)carbamate

To a solution of Intermediate I-97 (784 mg, 2.91 mmol) and pyridine(1.961 mL, 24.25 mmol) in DCM (48.5 mL, 0.05 M) was added crudeIntermediate I-88A (820 mg, 2.425 mmol) dropwise from its own solutionof DCM (48.500 mL). [Note: Addition funnel was used to add solution over10 min]. Following the reagent addition, the reaction mixture wasconcentrated down to remove excess pyridine and purified by ISCO (0-100%EtOAc/Hex, product at 35%) to afford Intermediate I-88B (1.10 g, 1.63mmol, 67% yield) as an off-white solid. LC-MS: Method H, RT=1.29 min, MS(ESI) m/z: 571.0, 573.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.67-8.49 (m,2H), 7.66 (dd, J=11.0, 3.5 Hz, 1H), 7.41-7.34 (m, 1H), 5.12 (dd, J=6.5,3.0 Hz, 1H), 4.55 (dd, J=6.3, 3.0 Hz, 1H), 4.45-4.39 (m, 2H), 3.98 (t,J=5.5 Hz, 2H), 1.34 (d, J=6.4 Hz, 3H), 1.28 (d, J=6.6 Hz, 3H), 0.92-0.86(m, 9H), 0.08 (s, 6H).

Intermediate I-88

To a solution of Intermediate I-88B (95 mg, 0.166 mmol) in THF (3327 μl)was added 1 M HCl (832 μl, 0.832 mmol) at room temperature (12 pm).After 1.5 h, the reaction was quenched with saturated NaHCO₃, dilutedwith EtOAc, extracted, dried over MgSO₄, filtered, concentrated, andpurified by ISCO (12 g, 0-100% EtOAc/DCM, product at 85%) to affordIntermediate I-88 (50 mg, 0.109 mmol, 65.8% yield) as a colorless oil.LC-MS: Method H, RT=0.91 min, MS (ESI) m/z: 456.9, 458.9 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.61 (br. s., 2H), 7.64 (d, J=11.0 Hz, 1H), 7.43-7.32(m, 1H), 7.00 (br. s., 1H), 5.12 (qd, J=6.5, 3.0 Hz, 1H), 4.56 (qd,J=6.4, 3.1 Hz, 1H), 4.51-4.44 (m, 2H), 4.23 (t, J=6.3 Hz, 1H), 3.98 (m,2H), 1.43 (d, J=6.4 Hz, 3H), 1.39 (d, J=6.4 Hz, 3H).

Intermediate I-89 methyl5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinate

This intermediate was prepared in a manner analogous to IntermediateI-82. Thus, Intermediate I-80 was reacted with methyl 5-aminopicolinateand purified by ISCO (0-100% EtOAc/DCM, product at 35%) to affordIntermediate I-89 (76% yield) as a yellow solid. LC-MS: Method H,RT=1.31 min, MS (ESI) m/z: 606.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.55(s, 2H), 8.47 (s, 1H), 8.20-8.11 (m, 1H), 8.10-8.05 (m, 1H), 7.78 (d,J=11.4 Hz, 1H), 7.70 (dd, J=2.0, 0.9 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H),7.24 (s, 1H), 5.16 (qd, J=6.5, 3.0 Hz, 1H), 4.65-4.58 (m, 1H), 4.55 (q,J=7.0 Hz, 2H), 3.95 (s, 3H), 2.62 (s, 3H), 1.49 (t, J=7.0 Hz, 3H), 1.46(d, J=6.6 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H).

Intermediate I-90 methyl5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate

This intermediate was prepared in a manner analogous to IntermediateI-82. Thus, Intermediate I-80 was reacted with Intermediate I-107 andpurified by ISCO (0-80% EtOAc/DCM, product at 40%) to affordIntermediate I-90 (81% yield) as a yellow solid. LC-MS: Method H,RT=1.24 min, MS (ESI) m/z: 607.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.04(s, 2H), 8.53 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 7.77 (d, J=11.2 Hz, 1H),7.70 (dd, J=1.8, 0.9 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.45 (s, 1H), 5.17(qd, J=6.5, 2.9 Hz, 1H), 4.65-4.58 (m, 1H), 4.58-4.51 (m, 2H), 4.02 (s,3H), 2.62 (s, 3H), 1.49 (t, J=7.0 Hz, 3H), 1.46 (d, J=6.6 Hz, 3H), 1.40(d, J=6.6 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −132.68 (s, 1F).

Intermediate I-91(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan

This intermediate was prepared in a manner analogous to IntermediateI-78. Thus, Intermediate I-72A was reacted with Intermediate I-121 andpurified by ISCO (0-70% EtOAc/DCM, product at 30%) to afford I-91 (55%yield) as a yellow solid. LC-MS: Method H, RT=1.16 min, MS (ESI) m/z:433.0, 435.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (d, J=3.1 Hz, 1H),8.65 (d, J=2.4 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.03-7.94 (m, 3H), 4.89(d, J=5.1 Hz, 1H), 4.43-4.34 (m, 1H), 4.01 (s, 3H), 3.88-3.77 (m, 1H),1.32 (d, J=6.2 Hz, 3H), 1.20 (d, J=6.2 Hz, 3H)¹⁹F NMR (376 MHz, DMSO-d₆)δ −133.13 (s, 1F).

Intermediate I-92 1-(5-aminopyridin-2-yl)-2-methylpropan-2-ol

Intermediate I-92A: 1-(5-bromopyridin-2-yl)-2-methylpropan-2-ol

5-bromo-2-methylpyridine (0.7 g, 4.07 mmol) was dissolved in anhydrousTHF (20 mL). The solution was cooled to −78° C. and 2M LDA in THF (2.442mL, 4.88 mmol) was added dropwise. The reaction mixture was stirred for20 minutes at −78° C. then freshly distilled acetone (1.046 mL, 14.24mmol) was added and the reaction mixture continued to stir for 20minutes at −78° C. The reaction mixture was then quenched with saturatedammonium chloride and extracted with EtOAc (3×). The combined organiclayer was washed with brine (1×), dried with sodium sulfate, filteredand concentrated. The resulting residue was dissolved in a small amountof methylene chloride before being charged to a 24 g silica gelcartridge which was eluted with a 15 min gradient from 0-100% EtOAc inhexane, The desired fractions were collected and concentrated to yieldIntermediate I-92A (0.432 g, 1.877 mmol, 46.1% yield). LC-MS: Method H,MS (ESI) m/z: 232.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=2.2 Hz,1H), 7.79 (dd, J=8.1, 2.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.91 (s, 2H),1.28-1.17 (m, 6H).

Intermediate I-92

To a solution of Intermediate I-92A (432 mg, 1.877 mmol) dissolved inDMSO (5 mL) was added L-proline (86 mg, 0.751 mmol), ammonium hydroxide(0.146 mL, 3.75 mmol), potassium carbonate (519 mg, 3.75 mmol) andcopper(I) iodide (71.5 mg, 0.375 mmol). The reaction vessel wasevacuated and backfilled with Ar 3× then stirred at 90° C. for 18 h. Thereaction mixture was then diluted with water and extracted with EtOAc(3×). The combined organic layer was washed with brine, dried withsodium sulfate, filtered and concentrated. The resulting residue wasdissolved in methylene chloride before being charged to a 24 g silicagel cartridge which was eluted with a 15 min gradient from 0-30% MeOH inmethylene chloride. The desired fractions were collected andconcentrated to yield Intermediate I-92 (47 mg, 0.283 mmol, 15% yield),as a white solid. LC-MS: Method H, MS (ESI) m/z: 167.1 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.04 (d, J=2.6 Hz, 1H), 7.00-6.96 (m, 1H), 6.95-6.90(m, 1H), 2.81 (s, 2H), 1.22 (s, 6H).

Intermediate I-936-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-amine

Intermediate I-93A: 2-((5-nitropyridin-2-yl)oxy)ethanol

Ethylene glycol (0.883 mL, 15.84 mmol) was dissolved in DMF (10 mL) at0° C. Sodium hydride (253 mg, 6.33 mmol, 60% in mineral oil) was addedto the reaction mixture portion wise and the reaction mixture wasstirred for 10 minutes at 0° C. 2-fluoro-5-nitropyridine (450 mg, 3.17mmol) dissolved in 1 mL of DMF was then added to the reaction mixturewhich was allowed to stir for 15 minutes at room temperature. Themixture was then quenched with saturated ammonium chloride and extractedwith EtOAc (1×). The organic layer was then washed with 10% aqueous LiCl(3×), brine (1×), dried with sodium sulfate, filtered and concentratedto yield Intermediate I-93A, (530 mg, 2.88 mmol, 91% yield), as a clearoil which was brought forward without further purification. LC-MS:Method H, MS (ESI) m/z: 185.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.09 (d,J=2.9 Hz, 1H), 8.41 (dd, J=9.0, 2.9 Hz, 1H), 6.92 (dd, J=9.2, 0.4 Hz,1H), 4.65-4.54 (m, 2H), 4.09-3.96 (m, 2H), 2.32 (t, J=5.9 Hz, 1H).

Intermediate I-93B:2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyridine

Intermediate I-93A (530 mg, 2.88 mmol) was dissolved in dichloromethane(20 mL) along with TEA (0.521 mL, 3.74 mmol) and DMAP (70.3 mg, 0.576mmol). TBS-Cl (521 mg, 3.45 mmol) was added to the reaction mixturewhich was allowed to stir at room temperature for 18 h. The reactionmixture was then quenched with saturated aqueous sodium bicarbonate andextracted with DCM (2×). The organic layer was washed with brine (1×),dried with sodium sulfate, filtered and concentrated. The resultingresidue was dissolved in methylene chloride before being charged to a 40g silica gel cartridge which was eluted with a 15 min gradient from0-100% EtOAc in hexane. The desired fractions were collected andconcentrated to yield Intermediate I-93B, (700 mg, 2.346 mmol, 82%yield), as a clear oil. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z:299.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.98 (d, J=2.4 Hz, 1H), 8.27(dd, J=9.0, 2.9 Hz, 1H), 6.80-6.72 (m, 1H), 4.47-4.35 (m, 2H), 3.90 (dd,4.5 Hz, 2H), 0.84-0.73 (m, 9H), 0.03-0.01 (m, 6H).

Intermediate I-93

Intermediate I-93B (700 mg, 2.346 mmol) was dissolved in ethyl acetate(10 mL). Pd—C (125 mg, 0.117 mmol, 10% by wt.) was added to the reactionmixture which was evacuated and backfilled with 1 atm of hydrogen 3× andstirred under 1 atm of hydrogen at room temperature for 3 h. Thereaction mixture was then filtered through a pad of celite and thefiltrate was concentrated to yield Intermediate I-93, (561 mg, 2.090mmol, 89% yield), as a yellow oil. The product was brought forwardwithout further purification. LC-MS: Method H, MS (ESI) m/z: 289.2(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.59-7.53 (m, 1H), 7.01-6.86 (m, 1H),6.58-6.47 (m, 1H), 4.27-4.14 (m, 2H), 3.96-3.80 (m, 2H), 3.37-3.11 (m,2H), 0.86-0.77 (m, 10H), 0.00 (s, 6H).

Intermediate I-942-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-4-amine

Intermediate I-94A: 2-(4-bromopyridin-2-yl)ethanol

4-bromo-2-methylpyridine (2.5 g, 14.53 mmol) was dissolved in anhydrousTHF (50 mL) at −78° C. LDA (25.4 mL, 50.9 mmol) was added to thereaction mixture which was allowed to stir at −78° C. for 30 minutes.Anhydrous DMF (3.38 mL, 43.6 mmol) was then added to the reactionmixture which continued to stir at −78° C. for an additional 45 minutes.A mixture of acetic acid (3.33 mL, 58.1 mmol)/MeOH (10 mL) was thenadded to the mixture at −78° C. followed by sodium borohydride (0.550 g,14.53 mmol). The reaction mixture was then allowed to warm to roomtemperature and was stirred for 1 h then quenched with 10% aqueouscitric acid solution at room temperature and stirred for an additional10 minutes. The reaction mixture was extracted with EtOAc (3×). Theorganic layer was washed with brine (1×), dried with sodium sulfate,filtered and concentrated to yield Intermediate I-94A which was broughtforward without further purification. LC-MS: Method H, MS (ESI) m/z:201.9 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J=5.3 Hz, 1H), 7.58(d, J=1.8 Hz, 1H), 7.49 (dd, J=5.4, 1.9 Hz, 1H), 3.78-3.70 (m, 1H),2.89-2.86 (m, 2H), 2.28 (d, J=5.5 Hz, 1H).

Intermediate I-94B: 2-(4-bromopyridin-2-yl)ethyl acetate

Intermediate I-94A (2.9 g, 14.35 mmol) was dissolved in THF (50 mL).Acetic anhydride (4.06 mL, 43.1 mmol) was added to the reaction mixturefollowed by DMAP (0.351 g, 2.87 mmol) and pyridine (3.48 mL, 43.1 mmol).The mixture was stirred at room temperature for 2 hours then dilutedwith EtOAc and 1.5M potassium diphosphate solution and extracted withEtOAc (3×). The organic layer was washed with brine (1×), dried withsodium sulfate, filtered and concentrated. The resulting residue wasdissolved in methylene chloride before being charged to an 80 g silicagel cartridge which was eluted with a 30 min gradient from 0-80% EtOAcin hexane. The desired fractions were collected and concentrated toyield Intermediate I-94B (0.98 g, 4.01 mmol, 28.0% yield) as a yellowoil. LC-MS: Method H, MS (ESI) m/z: 246.0 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.40 (d, J=5.5 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 7.36 (dd,J=5.3, 1.8 Hz, 1H), 4.48 (t, J=6.6 Hz, 2H), 3.11 (t, J=6.6 Hz, 2H),2.08-1.99 (m, 3H).

Intermediate I-94

Intermediate I-94B (282 mg, 3.20 mmol), 2,2,2-trifluoroacetamide (722mg, 6.39 mmol), 2-(4-bromopyridin-2-yl)ethyl acetate (780 mg, 3.20mmol), 3 Å molecular sieves (250 mg, 3.20 mmol), copper(I) iodide (122mg, 0.639 mmol) and potassium carbonate (883 mg, 6.39 mmol) weredissolved in dioxane (1 mL). The reaction vessel was evacuated andbackfilled with Ar 3× then heated to 75° C. for 4 h. 5 mL of MeOH wasthen added to the reaction mixture which was allowed to stir for 30minutes at room temperature. The reaction mixture was then filteredthrough celite and the filtrate was concentrated. The resulting residuewas dissolved in THF (30 mL). 1M aqueous LiOH (12.05 mL, 12.05 mmol) wasadded to the mixture which was allowed to stir at room temperature for18 h. The reaction mixture was then concentrated to dryness, redissolvedin THF (30 mL) and filtered through a pad of celite. The celite pad waswashed with excess THF. To the THF solution (˜50 mL) was added TBS-Cl(3028 mg, 20.09 mmol) and imidazole (1368 mg, 20.09 mmol). The reactionmixture was stirred at room temperature for 1 hour then filtered througha pad of celite and the filtrate was concentrated. The resulting residuewas dissolved in methylene chloride before being charged to an 80 gsilica gel cartridge which was eluted with a 30 min gradient from 0-25%MeOH in methylene chloride. The fractions containing desired productwere concentrated and the resulting isolate was repurified on an 80 gcolumn using 1M NH₃ MeOH/DCM (0-20%, 30 min gradient). Fractionscontaining the desired product were concentrated to yield IntermediateI-94 (293 mg, 1.16 mmol, 29% yield). LC-MS: Method H, MS (ESI) m/z:253.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, J=5.7 Hz, 1H), 6.51 (d,J=2.2 Hz, 1H), 6.44 (dd, J=5.6, 2.3 Hz, 1H), 4.35-4.11 (m, 2H), 3.97 (t,J=6.6 Hz, 2H), 2.91 (t, J=6.5 Hz, 2H), 0.88 (s, 9H), 0.00 (s, 6H).

Intermediate I-95 1-(4-aminopyridin-2-yl)-2-methylpropan-2-ol

Intermediate I-95A: 1-(4-bromopyridin-2-yl)-2-methylpropan-2-ol

To a stirred solution of 4-bromo-2-methylpyridine (0.7 g, 4.07 mmol) inanhydrous THF (20 mL) at −78° C. was added 2M LDA in THF (2.442 mL, 4.88mmol) dropwise. The reaction mixture was stirred for 20 minutes at −78°C. Freshly distilled acetone (1.046 mL, 14.24 mmol) was then added tothe reaction mixture which stirred for an additional 20 minutes at −78°C. The reaction mixture was then quenched with saturated ammoniumchloride and was allowed to warm to room temperature. The reactionmixture was then diluted with water and extracted with EtOAc (3×). Theorganic layer was washed with brine (1×), dried with sodium sulfate,filtered and concentrated. The resulting residue was dissolved inmethylene chloride before being charged to a 24 g silica gel cartridgewhich was eluted with a 15 min gradient from 0-100% EtOAc in hexane. Thedesired fractions were collected and concentrated to yield IntermediateI-95A (0.588 g, 2.56 mmol, 62.8% yield). LC-MS: Method H, MS (ESI) m/z:232.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J=5.3 Hz, 1H),7.42-7.34 (m, 2H), 5.35-5.01 (m, 1H), 2.92 (s, 2H), 1.25 (s, 6H).

Intermediate I-95

Intermediate I-95A (588 mg, 2.56 mmol) was dissolved in DMSO (5 mL)along with L-proline (118 mg, 1.022 mmol), ammonium hydroxide (0.199 mL,5.11 mmol), potassium carbonate (706 mg, 5.11 mmol) and copper(I) iodide(97 mg, 0.511 mmol). The reaction mixture was evacuated and backfilledwith argon three times before being sealed and heated to 90° C. for 5hours. The reaction mixture was then filtered through celite, washedwith MeOH and the filtrate was concentrated. The resulting residue wasdissolved in methylene chloride before being charged to a 24 g silicagel cartridge which was eluted with a 15 min gradient from 0-30% MeOH inmethylene chloride. Fractions containing desired product wereconcentrated and repurified by Prep HPLC using Method A to yieldIntermediate I-95 (28 mg, 0.168 mmol, 7% yield). LC-MS: Method H, MS(ESI) m/z: 167.0 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 7.94 (d, J=7.0 Hz,1H), 6.76 (dd, J=6.9, 2.3 Hz, 1H), 6.74-6.68 (m, 1H), 2.84 (s, 2H), 1.28(s, 6H).

Intermediate I-96 1-((4-aminopyridin-2-yl)oxy)-2-methylpropan-2-ol

Intermediate I-96A: 1-((4-bromopyridin-2-yl)oxy)-2-methylpropan-2-ol

This intermediate was prepared according to Procedure D from2-methylpropane-1,2-diol. Intermediate I-96A was afforded in 52% yieldafter column chromatography. LC-MS: Method H, MS (ESI) m/z: 247.9(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=5.5 Hz, 1H), 7.08 (dd,J=5.5, 1.5 Hz, 1H), 7.05 (d, J=1.3 Hz, 1H), 4.23 (s, 2H), 3.01 (s, 1H),1.34 (s, 6H).

Intermediate I-96

This intermediate was prepared from Intermediate I-96A according toProcedure E. Intermediate I-96 was afforded in 66% yield. LC-MS: MethodH, MS (ESI) m/z: 183.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.72-7.38 (m,1H), 6.24-6.15 (m, 1H), 6.14-5.95 (m, 2H), 5.91-5.80 (m, 1H), 3.91 (s,2H), 1.15 (s, 6H).

Intermediate I-972-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-amine

Intermediate I-97A: 2-((5-nitropyrimidin-2-yl)oxy)ethanol

2-chloro-5-nitropyrimidine (1 g, 6.27 mmol) was mixed with ethyleneglycol (8 ml, 143 mmol) and DIEA (3.28 ml, 18.81 mmol) was added. Themixture was stirred at 80° C. for 20 minutes and was then poured into 30mL of ice water. 40 mL of EtOAc was added to the mixture followed by 20mL of 1N aqueous HCl. EtOAc (30 mL×3) was used to extract the aqueouslayer. The combined organic layer was washed with brine, dried withsodium sulfate, filtered and concentrated to give Intermediate I-97A inquantitative yield as a yellow oil. The product was brought forwardwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 2H),4.73-4.51 (m, 2H), 4.08-3.96 (m, 2H), 2.41 (br. s., 1H).

Intermediate I-97B:2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-nitropyrimidine

Intermediate I-97A, (1.23 g, 6.64 mmol), was mixed withtert-butylchlorodimethylsilane (2.003 g, 13.29 mmol) in DCM (20 ml).Imidazole (0.905 g, 13.29 mmol) was added to the reaction mixture andthe reaction mixture stirred at room temperature for 30 minutes. Thesolid was filtered off and the filter cake was washed with a smallamount of DCM. The filtrate was mixed with 30 g of silica gel,evaporated to dryness and loaded on CombiFlash (80 g column, 0-50%EtOAc/Hexane) for purification. The fractions containing desired productwere collected and concentrated to give Intermediate I-97B, (1.73 g,5.78 mmol, 87% yield), as a light yellow solid. LC-MS: Method H, MS(ESI) m/z: 300.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.30 (2H, s),4.61 (2H, dd, J=5.50, 4.62 Hz), 4.02 (2H, dd, J=5.61, 4.73 Hz), 0.88(9H, s), 0.09 (6H, s).

Intermediate I-97

Intermediate I-97B, (1.73 g, 5.78 mmol), was dissolved in THF (40 ml).Wet Pd—C (0.307 g, 0.289 mmol, 10% by wt.) was then added to thesolution. The mixture was then evacuated and backfilled with hydrogen3×, and the mixture was stirred under 1 atm H₂ for 7 hours at roomtemperature. The catalyst was filtered off over a pad of celite whichwas washed with a small amount of EtOAc. The filtrate was concentratedto yield Intermediate I-97, (1.53 g, 5.68 mmol, 98% yield), as a graysolid. LC-MS: Method H, MS (ESI) m/z: 270.1 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.05 (2H, s), 4.35 (2H, t, J=5.50 Hz), 3.97 (2H, t, J=5.61Hz), 1.69 (2H, d, J=5.06 Hz), 0.89 (9H, s), 0.08 (6H, s).

Intermediate I-982-(2-((tert-butyldiphenylsilyl)oxy)ethyl)pyrimidin-5-amine

Intermediate I-98A: 3-hydroxypropanimidamide, HCl

To a mixture of MeOH (5 mL, 124 mmol)/toluene (30.1 mL) at 0° C. wasadded acetyl chloride (3.00 mL, 42.2 mmol) slowly over 10 minutes. Thereaction mixture was allowed to stir at 0° C. for 10 minutes then atroom temperature for 10 minutes. The reaction mixture was cooled to 0°C. and 3-hydroxypropanenitrile (1.5 g, 21.10 mmol) dissolved in 5 mL oftoluene added and the reaction mixture was allowed to stir at roomtemperature for 18 h. The reaction mixture was cooled to 0° C. and 7Nammonia in MeOH (15.07 mL, 106 mmol) was added carefully over 5 minutes.The reaction mixture was then allowed to warm to room temperature andstirred for 18 h at room temperature. The mixture was then filteredthrough celite and the filter cake washed with 2:1 toluene/MeOH. Thefiltrate was concentrated to yield Intermediate I-98A in quantitativeyield. The product was brought forward without further purification. ¹HNMR (400 MHz, DMSO-d₆) δ 3.70 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).

Intermediate I-98B: methyl 2-(2-hydroxyethyl)pyrimidine-5-carboxylate

Intermediate I-98A (8.9 g, 71.4 mmol) was dissolved in DMF (200 ml).While the solution stirred at room temperature, sodium(Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (16.5 g, 83mmol) was added in portion-wise and the reaction mixture was stirred atroom temperature for 18 h. The reaction mixture was then concentratedunder reduced pressure and heat. The resulting residue was thensuspended in 10:1 DCM:MeOH mixture and run through a pad of silicagel/celite which was washed with 500 mL of additional 10:1 DCM/MeOHsolution. The filtrate was concentrated to yield Intermediate I-98B(10.5 g, 57.6 mmol, 81% yield), as a red oil. The product was broughtforward without further purification. LC-MS: Method H, MS (ESI) m/z:183.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 2H), 4.69 (t, J=5.4Hz, 1H), 4.03-3.79 (m, 5H), 3.12 (t, J=6.6 Hz, 2H).

Intermediate I-98C: methyl2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)pyrimidine-5-carboxylate

To the solution of Intermediate I-98B (4 g, 21.96 mmol) in THF (80 mL)was added DMAP (0.134 g, 1.098 mmol), TEA (7.65 mL, 54.9 mmol) andTBDPS-Cl (8.46 mL, 32.9 mmol). The reaction mixture was stirred for 18 hat room temperature. 5 mL of methanol was then added and the reactionmixture stirred for 10 minutes at room temperature followed byevaporation under reduced pressure. The crude product was purified bysilica gel chromatography on a 120 g silica column using petroleumether, chloroform and EtOAc as eluent. First an eluent of 0-100%chloroform in petroleum ether was used followed by an eluent of 0-100%EtOAc in chloroform. Fractions containing desired product were collectedand concentrated to yield Intermediate I-98C (7.5 g, 17.9 mmol, 82%yield), as a colorless oil. LC-MS: Method H, MS (ESI) m/z: 421.2 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 9.16 (s, 2H), 7.73-7.28 (m, 10H), 4.22 (t,J=6.4 Hz, 2H), 3.97 (s, 4H), 3.30 (t, J=6.4 Hz, 2H), 0.98-0.94 (m, 9H).

Intermediate I-98D:2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)pyrimidine-5-carboxylic acid

Intermediate I-98C (2.14 g, 5.09 mmol) was dissolved in THF (60 mL). 1Maqueous LiOH (15.26 mL, 15.26 mmol) was added and the reaction mixturewas allowed to stir at room temperature for 1 hour. The majority of theTHF was concentrated under reduced pressure and the reaction mixture wasacidified with 10% citric acid to pH 4-5 then extracted 3× with EtOAc.The combined organic layer was washed with brine, dried with sodiumsulfate, filtered and concentrated to yield Intermediate I-98D, (2.07 g,5.09 mmol, 100% yield), as a clear glass. LC-MS: Method H, MS (ESI) m/z:407.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (s, 2H), 7.76-7.23 (m,10H), 4.19 (t, J=6.3 Hz, 2H), 3.25 (t, J=6.3 Hz, 2H), 0.90 (s, 9H).

Intermediate I-98

Intermediate I-98D (5.5 g, 13.53 mmol) was dissolved in THF (350 mL).TEA (9.43 mL, 67.6 mmol) was added to the mixture followed by diphenylphosphorazidate (9.31 g, 33.8 mmol) at room temperature. The reactionmixture was heated to 65° C. under a reflux condenser for 22 hours. Thereaction mixture was then allowed to cool to room temperature and water(175 mL) was added. The mixture was stirred at room temperature for 2hours and 15 minutes. The majority of THF was evaporated off underreduced pressure and the mixture was then diluted with water and a smallamount of brine and extracted 3× with a total of ˜500 mL of EtOAc. Theorganic layer was washed with brine, dried with sodium sulfate, filteredand concentrated. The resulting residue was dissolved in methylenechloride before being charged to a 330 g column which was eluted with agradient from 0-20% MeOH/DCM. Fractions containing desired product werecollected and concentrated to yield Intermediate I-98, (1.135 g, 3.01mmol, 22% yield), as an orange oil. LC-MS: Method H, MS (ESI) m/z:378.2. (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.04 (s, 2H), 7.59-7.53 (m,4H), 7.47-7.31 (m, 6H), 5.76 (s, 2H), 4.02 (t, J=6.7 Hz, 2H), 2.97 (t,J=6.7 Hz, 2H), 0.92 (s, 9H).

Intermediate I-996-(3-((tert-butyldimethylsilyl)oxy)-2,2-difluoropropoxy)pyridin-3-amine

Intermediate I-99A: 2,2-difluoro-3-((5-nitropyridin-2-yl)oxy)propan-1-ol

2,2-difluoropropane-1,3-diol (394 mg, 3.52 mmol) was dissolved in DMF(10 mL). Sodium hydride (77 mg, 1.934 mmol, 60% by wt.) was added to themixture at 0° C. and the reaction mixture was stirred at 0° C. for 10minutes. 2-fluoro-5-nitropyridine (250 mg, 1.758 mmol) dissolved in 1 mLof DMF was then added to the reaction mixture which was allowed to stirat room temperature for 1 hour. The mixture was then quenched withsaturated ammonium chloride and diluted with EtOAc. The organic layerwas washed with 10% aqueous LiCl (3×), and brine (1×), dried with sodiumsulfate, filtered and concentrated to yield2,2-difluoro-3-((5-nitropyridin-2-yl)oxy)propane as a yellow oil. To thecrude intermediate dissolved in DCM (9 mL) was added TEA (1137 μl, 8.16mmol) and DMAP (39.9 mg, 0.326 mmol) followed by TBS-Cl (738 mg, 4.89mmol). The reaction mixture stirred for 18 h at room temperature. 5 mLof MeOH was then added to the reaction mixture which was allowed to stirfor 10 minutes at room temperature. The reaction mixture was thenquenched with saturated sodium bicarbonate and extracted DCM (3×). Theorganic layer was washed with brine (1×), dried with sodium sulfate,filtered and concentrated. The resulting residue was dissolved in asmall amount of methylene chloride and charged to a 40 g silica gelcartridge which was eluted with a 15 min gradient from 0-100% EtOAc inhexane. Fractions containing desired product were concentrated to yieldIntermediate I-99A (204 mg, 0.586 mmol, 36% yield) as a clear oil.LC-MS: Method H, MS (ESI) m/z: 349.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ9.01 (dd, J=2.9, 0.4 Hz, 1H), 8.34 (dd, J=9.1, 2.8 Hz, 1H), 6.86 (dd,J=9.0, 0.4 Hz, 1H), 4.66 (t, J=12.4 Hz, 2H), 3.85 (t, J=12.2 Hz, 2H),0.81-0.78 (m, 9H), 0.00 (s, 6H).

Intermediate I-99

Intermediate I-99A (204 mg, 0.586 mmol) was dissolved in EtOAc (10 mL).Pd—C (18.69 mg, 0.176 mmol, 10% by wt.) was added to the solution andthe flask was evacuated and backfilled with 1 atm of hydrogen 3×. Thereaction mixture was stirred under 1 atm of hydrogen for 18 h and thenfiltered through celite and the celite pad washed with excess EtOAc. Thefiltrate was concentrated to yield Intermediate I-99 in quantitativeyield as a green oil. The product was brought forward without furtherpurification. LC-MS: Method H, MS (ESI) m/z: 319. (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.60-7.54 (m, 1H), 7.02-6.95 (m, 1H), 6.63-6.50 (m, 1H),4.45 (t, J=12.5 Hz, 2H), 3.86 (t, J=12.4 Hz, 2H), 0.81 (s, 9H), 0.00 (s,6H).

Intermediate I-100 4-((5-aminopyrimidin-2-yl)oxy)-2-methylbutan-2-ol,HCl

Intermediate I-100A: 4-((5-bromopyrimidin-2-yl)oxy)-2-methylbutan-2-ol

This intermediate was prepared according to Procedure A from3-methylbutane-1,3-diol. Intermediate I-100A was afforded in 68% yieldafter silica gel chromatography. LC-MS: Method H, MS (ESI) m/z: 263.0.¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 2H), 4.56 (t, J=6.8 Hz, 2H), 2.05 (t,J=6.8 Hz, 2H), 1.34 (s, 6H).

Intermediate I-100B:4-((5-((diphenylmethylene)amino)pyrimidin-2-yl)oxy)-2-methylbutan-2-ol

This intermediate was prepared according to Procedure B fromIntermediate I-100A. Intermediate I-100B was afforded in 81% yield aftersilica gel chromatography. LC-MS: Method H, MS (ESI) m/z: 362.1.

Intermediate I-100

Intermediate I-100 was afforded from Intermediate I-100B in 77% yieldaccording to Procedure C. LC-MS: Method H, MS (ESI) m/z: 198.1.

Intermediate I-1012-(2-methyl-2-((triethylsilyl)oxy)propoxy)pyrimidin-5-amine

Intermediate I-101A: 1-((5-bromopyrimidin-2-yl)oxy)-2-methylpropan-2-ol

This intermediate was prepared according to Procedure A from2-methylpropane-1,2-diol. Intermediate I-101A was afforded in 29% yieldafter silica gel chromatography. LC-MS: Method H, MS (ESI) m/z: 249.0.¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 2H), 4.25 (s, 2H), 1.38 (s, 6H).

Intermediate I-101B:1-((5-((diphenylmethylene)amino)pyrimidin-2-yl)oxy)-2-methylpropan-2-ol

This intermediate was prepared according to Procedure B fromIntermediate I-101A. Intermediate I-101B was afforded in 58% yield aftersilica gel chromatography. LC-MS: Method H, MS (ESI) m/z: 348.2. ¹H NMR(400 MHz, CDCl₃) δ 7.99 (s, 2H), 7.81-7.67 (m, 2H), 7.58-7.35 (m, 6H),7.19-7.02 (m, 2H), 4.17 (s, 2H), 1.34 (s, 6H).

Intermediate I-101

Intermediate I-101B (152 mg, 0.438 mmol) was dissolved in MeOH (5mL)/THF (5.00 mL). 1M HCl (1.0 mL, 1.0 mmol) was added to the reactionmixture and the reaction mixture was stirred for 30 minutes at roomtemperature. The mixture was then concentrated under reduced pressureand azeotroped with toluene 3×. The resulting residue was dissolved inanhydrous DCM (5 mL) along with Hunig's Base (0.534 mL, 3.06 mmol). Thereaction mixture was then cooled to 0° C. and triethylsilyltrifluoromethanesulfonate (347 mg, 1.311 mmol) was added dropwise andthe reaction mixture was allowed to stir at 0° C. for 30 minutes andthen at room temperature for 30 minutes. The mixture was then quenchedwith saturated sodium bicarbonate and extracted with DCM (3×). Theorganic layer was washed with brine (1×), dried with sodium sulfate,filtered and concentrated. The resulting residue was dissolved inmethylene chloride before being charged to a 24 g silica gel cartridgewhich was eluted with a 15 min gradient from 0-25% MeOH in methylenechloride. The desired fractions were collected and concentrated to yieldIntermediate I-101 (42 mg, 0.141 mmol, 32.3% yield). LC-MS: Method H, MS(ESI) m/z: 298.2. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 2H), 4.08 (s, 2H),1.38 (s, 6H), 0.98-0.93 (m, 6H), 0.67-0.57 (m, 9H).

Intermediate I-102 1-(5-aminopyrimidin-2-yl)-2-methylpropan-2-ol

Intermediate I-102A: 3-hydroxy-3-methylbutanimidamide, HCl

This intermediate was synthesized from 3-hydroxy-3-methylbutanenitrileusing the method described to synthesize Intermediate I-98A.Intermediate I-102A was afforded in quantitative yield. ¹H NMR (400 MHz,DMSO-d₆) δ 2.54 (s, 2H), 1.36-1.00 (m, 6H).

Intermediate I-102B: methyl2-(2-hydroxy-2-methylpropyl)pyrimidine-5-carboxylate

This intermediate was synthesized from I-102A using the proceduredescribed for Intermediate I-98B. Intermediate I-102B was afforded in58% yield after chromatography. LC-MS: Method H, MS (ESI) m/z: 211.0(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (s, 2H), 4.70 (s, 1H), 3.91 (s,3H), 3.09 (s, 2H), 1.17 (s, 6H).

Intermediate I-102C: methyl2-(2-methyl-2-((triethylsilyl)oxy)propyl)pyrimidine-5-carboxylate

To a solution of Intermediate I-102B (0.7 g, 3.33 mmol) and 2,6-lutidine(0.776 ml, 6.66 mmol) in DCM (16.65 ml) was added triethylsilyltrifluoromethanesulfonate (1.408 g, 5.33 mmol) dropwise at 0° C. Thereaction mixture was allowed to stir at 0° C. for 30 minutes. Thereaction mixture was quenched with saturated sodium bicarbonate andextracted with DCM (3×). The combined organic layer was washed withbrine, dried with sodium sulfate, filtered and concentrated. Theresulting residue was dissolved in a small amount of methylene chlorideand charged to a 40 g silica gel cartridge which was eluted with a 15min gradient from 0-100% EtOAc in hexane. Fractions containing thedesired product were concentrated to yield Intermediate I-102C (0.629 g,1.938 mmol, 58% yield) as a clear oil. LC-MS: Method H, MS (ESI) m/z:325.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 4.00 (s, 3H), 3.24(s, 2H), 1.37 (s, 6H), 0.94-0.81 (m, 9H), 0.56 (q, J=8.1 Hz, 7H).

Intermediate I-102D:2-(2-methyl-2-((triethylsilyl)oxy)propyl)pyrimidine-5-carboxylic acid

Intermediate I-102C (0.629 g, 1.938 mmol) was dissolved in THF (20 mL).1M aqueous LiOH (5.82 mL, 5.82 mmol) was added to the reaction mixturewhich was allowed to stir at room temperature for 1 hour. Most of theTHF was evaporated off and the reaction mixture was acidified to pH 4-5with 10% citric acid and extracted with EtOAc (3×). The combined organiclayer was washed with brine, filtered and concentrated to yieldIntermediate I-102D (0.6 g, 1.623 mmol, 84% yield) as a clear glass.LC-MS: Method H, MS (ESI) m/z: 311.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.14 (s, 2H), 3.13 (s, 2H), 1.31 (s, 6H), 0.84 (t, J=7.9 Hz, 9H),0.53-0.40 (m, 6H).

Intermediate I-102

This intermediate was synthesized from I-102D according to the proceduredescribed for conversion of Intermediate I-98D to Intermediate I-98.Intermediate I-102 was afforded in 78% yield after chromatography.LC-MS: Method H, MS (ESI) m/z: 168.1 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ8.16 (s, 2H), 2.94 (s, 2H), 1.22 (s, 6H).

Intermediate I-103(R)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidin-5-amine

This intermediate was prepared from (R)-ethyl 2-hydroxypropanoate in thesame manner as described for Intermediate I-104 below. LC-MS: Method H,MS (ESI) m/z: 284.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 2H),4.20-4.06 (m, 2H), 4.01-3.93 (m, 1H), 3.29 (br. s., 2H), 1.17 (d, J=6.2Hz, 3H), 0.81 (s, 9H), 0.01 (d, J=6.2 Hz, 6H). MS (ESI) m/z: 284.2(M+H)⁺.

Intermediate I-104(S)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidin-5-amine

Intermediate I-104A: (S)-ethyl2-((tert-butyldimethylsilyl)oxy)propanoate

(S)-ethyl 2-hydroxypropanoate (1.50 g, 12.70 mmol) was reacted accordingto Procedure I using DCM as a solvent to afford Intermediate I-104A (2.3g, 9.90 mmol, 78% yield) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ4.35-4.28 (m, 1H), 4.18 (t, J=7.5 Hz, 2H), 1.40 (d, J=6.8 Hz, 3H), 1.28(t, J=7.2 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H).

Intermediate I-104B: (S)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol

Intermediate I-104A (2.2 g, 9.47 mmol) was dissolved in THF (100 ml) andthe solution was cooled to −78° C. To the reaction mixture was addedDIBAL-H (23.67 ml, 23.67 mmol) and the reaction mixture was allowed towarm to room temperature and stirred for 3 h at room temperature beforebeing quenched with saturated Rochelle's salt. The quenched reactionmixture was stirred for 18 h at room temperature and then extracted withEtOAc (3×). The combined organic layer was washed with brine, dried withsodium sulfate, filtered and concentrated under reduced pressure toyield Intermediate I-104B in quantitative yield. ¹H NMR (400 MHz, CDCl₃)δ 3.87-3.77 (m, J=2.6 Hz, 1H), 3.46-3.37 (m, 1H), 3.32-3.21 (m, 1H),1.03 (d, J=6.4 Hz, 3H), 0.82 (s, 9H), 0.00 (s, 6H).

Intermediate I-104C:(S)-5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidine

Triphenylphosphine (2.88 g, 10.98 mmol) was dissolved in THF (143 ml)and the solution was cooled to 0° C. DIAD (1.941 ml, 9.98 mmol) wasadded and reaction mixture was allowed to stir for 5 minutes at 0° C.Intermediate I-104B (1.9 g, 9.98 mmol) was added to the reaction mixtureand the reaction mixture was allowed to stir for 10 minutes at 0° C.5-bromopyrimidin-2-ol (1.5 g, 8.57 mmol) was then added to the reactionmixture which was allowed to warm to room temperature slowly and stirredfor 72 hours at room temperature. The reaction mixture was then dilutedwith water and extracted with EtOAc (3×). The combined organic layer waswashed with brine (1×), dried with sodium sulfate, filtered andconcentrated. The resulting residue was dissolved in a small amount ofmethylene chloride before being charged to an 80 g silica gel cartridgewhich was eluted with a 30 min gradient from 0-100% EtOAc in hexane.Fractions containing desired product were collected and concentrated toyield Intermediate I-104C (1.9 g, 5.47 mmol, 55% yield). ¹H NMR (400MHz, CDCl₃) δ 8.52 (s, 2H), 4.34-4.26 (m, 1H), 4.18 (s, 1H), 4.15-4.05(m, 1H), 1.24 (d, J=6.2 Hz, 3H), 0.87 (s, 9H), 0.07 (d, J=8.1 Hz, 5H).LC-MS: Method H, MS (ESI) m/z: 349.1 (M+H)⁺.

Intermediate I-104D(S)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)-N-(diphenylmethylene)pyrimidin-5-amine

This intermediate was synthesized from Intermediate I-104C usingProcedure B. Intermediate I-104D was afforded in 78% yield afterchromatography. LC-MS: Method H, MS (ESI) m/z: 448.2 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.95 (s, 2H), 7.78-7.71 (m, 2H), 7.53-7.30 (m, 6H),7.16-7.06 (m, 2H), 4.31-4.11 (m, 2H), 4.08-4.01 (m, 1H), 1.22 (d, J=5.9Hz, 3H), 0.87 (s, 9H), 0.05 (d, J=9.9 Hz, 6H).

Intermediate I-104

Intermediate I-104D (1.9 g, 4.24 mmol) was dissolved in 90:10:0.1MeOH/water/TFA (14 ml) and the solution stirred for 15 minutes at roomtemperature then basified with 1.5 M dipotassium phosphate solution andextracted with EtOAc (3×). The combined organic layer was washed withbrine (1×), dried with sodium sulfate, filtered and concentrated. Theresulting residue was dissolved in methylene chloride and charged to an80 g silica gel cartridge which was eluted with a 30 min gradient from0-15% MeOH in methylene chloride. Fractions containing the desiredproduct were concentrated to yield Intermediate I-104 (210 mg, 0.741mmol, 17% yield). LC-MS: RT=1.01 min, LC-MS: Method H, MS (ESI) m/z:284.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (s, 2H), 4.93 (s, 2H),4.16-3.83 (m, J=7.4, 5.6 Hz, 3H), 1.12 (d, J=6.2 Hz, 3H).

Intermediate I-105(S)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)pyrimidin-5-amine

This intermediate was prepared from (S)-propane-1,2-diol using the samereaction sequence as described for Intermediate I-106 below. LC-MS:Method H, MS (ESI) m/z: 284.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s,2H), 5.04 (d, J=6.2 Hz, 1H), 3.78 (dd, J=10.3, 5.5 Hz, 1H), 3.60 (dd,J=10.3, 5.7 Hz, 1H), 1.28 (d, J=6.4 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 3H),−0.03 (s, 3H).

Intermediate I-106(R)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)pyrimidin-5-amine

Intermediate I-106A: (R)-2-((5-nitropyrimidin-2-yl)oxy)propan-1-ol,(R)-1-((5-nitropyrimidin-2-yl)oxy)propan-2-ol

To a vial containing 2-chloro-5-nitropyrimidine (300 mg, 1.9 mmol) wasadded DMF (3 mL) followed by (R)-propane-1,2-diol (0.5 mL, 6.81 mmol).Potassium carbonate (520 mg, 3.76 mmol) was then added to the reactionmixture which was allowed to stir vigorously at 65° C. for 1 h. Thereaction mixture was then quenched with acetic acid (0.323 mL, 5.64mmol), diluted with EtOAc and filtered over a pad of silica gel. Thefiltrate was concentrated before being purified by ISCO (40 g GoldColumn, 0-100% EtOAc/Hex) to afford Intermediate I-106A as a mixture ofregioisomers (64 mg, 0.32 mmol, 17% yield). LC-MS: Method H, MS (ESI)m/z: 199.6 (M+H)⁺.

Intermediate I-106B:(R)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)-5-nitropyrimidine

Intermediate I-106A (64.0 mg, 0.321 mmol) was dissolved in THF (5 mL)along with TEA (0.224 mL, 1.607 mmol) and DMAP (7.85 mg, 0.064 mmol).TBS-Cl (242 mg, 1.607 mmol) was added to the reaction mixture which wasallowed to stir for 18 h at room temperature. The reaction mixture wasthen concentrated and the resulting residue was dissolved in a smallamount of methylene chloride and charged to a 24 g silica gel cartridgewhich was eluted with a 15 min gradient from 0-100% EtOAc in hexane.Fractions containing the desired product concentrated to yieldIntermediate I-106B (67 mg, 0.214 mmol, 66.5% yield). LC-MS: Method H,MS (ESI) m/z: 314.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 2H), 5.38(d, J=4.8 Hz, 1H), 3.83-3.64 (m, 2H), 0.80-0.77 (m, 9H), 0.00 (s, 3H),−0.03 (s, 3H). MS (ESI) m/z 314.1 (M+H).

Intermediate I-106

Intermediate I-106B (67 mg, 0.214 mmol) was dissolved in EtOAc (10 mL).Wet Pd—C (22.75 mg, 0.021 mmol, 10% by wt.) was added to the reactionmixture which was allowed to stir under 1 atm of hydrogen for 6 hours atroom temperature. The reaction mixture was then filtered through celite.The filtrate was concentrated to yield Intermediate I-106 (55 mg, 0.194mmol, 91% yield). The product was brought forward without furtherpurification. LC-MS: Method H, MS (ESI) m/z: 284.2 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.97 (s, 2H), 5.11-4.82 (m, 1H), 3.80-3.73 (m, 1H),3.64-3.52 (m, 1H), 3.28 (br. s., 2H), 1.28 (d, J=6.2 Hz, 3H), 0.83-0.77(m, 9H), 0.00 (s, 3H), −0.03 (s, 3H).

Intermediate I-107 Methyl 5-aminopyrimidine-2-carboxylate

Intermediate I-107A: methyl5-((diphenylmethylene)amino)pyrimidine-2-carboxylate

5-bromopyrimidine-2-carboxylate was reacted according to Procedure B toafford Intermediate I-107A (3.1 g, 9.77 mmol, 70.7% yield) as a yellowsolid. LC-MS: Method H, MS (ESI) m/z: 318.1 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.33 (s, 2H), 7.82 (d, J=6.3 Hz, 2H), 7.72-7.32 (m, 6H), 7.13(br. s., 2H), 4.04 (s, 3H).

Intermediate I-107

Intermediate I-107A (0.2 g, 0.630 mmol) was solvated in a mixture of THF(5 ml) and MeOH (5.00 ml). To this solution was added 1M aqueous HCl(1.576 ml, 1.576 mmol). After 30 minutes of stirring at room temperaturethe reaction mixture was diluted with water and the aqueous phase waswashed with 4:1 EtOAc/Hexanes (3×) then concentrated to afford theaminopyrimidine HCl salt intermediate. This crude intermediate wasdissolved in MeOH and run through solid supported HCO₃ ⁻ cartridge(PL-HCO3 MP SCE) to form the free base. The cartridge was washed withMeOH and the resulting solution was concentrated to yield IntermediateI-107 (0.065 g, 0.42 mmol, 67% yield). LC-MS: Method H, MS (ESI) m/z:154.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 2H), 6.38 (s, 2H),3.80 (s, 3H).

Intermediate I-108 4-((4-aminopyridin-2-yl)oxy)-2-methylbutan-2-ol

Intermediate I-108A: 4-((4-bromopyridin-2-yl)oxy)-2-methylbutan-2-ol

This intermediate was prepared according to Procedure D from3-methylbutane-1,3-diol. Intermediate I-108A was afforded in 80% yieldafter chromatography. LC-MS: Method H, MS (ESI) m/z: 261.9. (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.00 (d, J=5.5 Hz, 1H), 7.05 (dd, J=5.5, 1.8 Hz,1H), 6.96 (d, J=1.5 Hz, 1H), 4.52 (t, J=6.5 Hz, 2H), 2.00 (t, J=6.5 Hz,2H), 1.32 (s, 6H).

Intermediate I-108

Intermediate I-108 was prepared from Intermediate I-108A according toProcedure E. Intermediate I-108 was afforded in 61% yield afterchromatography. LC-MS: Method H, MS (ESI) m/z: 197.0. ¹H NMR (400 MHz,DMSO-d₆) δ 7.60 (d, J=5.7 Hz, 1H), 6.14 (dd, J=5.7, 2.0 Hz, 1H), 5.89(s, 2H), 5.77 (d, J=1.8 Hz, 1H), 4.33 (s, 1H), 4.21 (t, J=7.4 Hz, 2H),1.76 (t, J=7.4 Hz, 2H), 1.13 (s, 6H).

Intermediate I-1096-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-amine

Intermediate I-109A: methyl 2-(5-nitropyridin-2-yl)acetate

Tert-butyl methyl malonate (2.64 g, 15.14 mmol) was dissolved in THF (50mL). Sodium hydride (0.605 g, 15.14 mmol) was added portion-wise at 0°C. and the reaction mixture was allowed to stir for 15 min at roomtemperature. 2-chloro-5-nitropyridine (2.0 g, 12.61 mmol) dissolved in10 mL of THF was then added to the mixture and the mixture was allowedto stir for 4 hours at room temperature before being quenched withsaturated aqueous ammonium chloride and extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried with sodium sulfate,filtered and concentrated. The resulting residue was dissolved in 30 mLof 2:1 DCM/TFA and stirred for 1.5 hours. The reaction mixture was thendiluted with 1.5 M potassium phosphate solution and extracted with EtOAc(3×). The combined organic layer was washed with brine, dried withsodium sulfate, filtered and concentrated. The resulting residue wasdissolved in methylene chloride before being charged to an 80 g silicagel cartridge which was eluted with a 30 min gradient from 0-100% EtOAcin hexane. Fractions containing the desired product were concentrated toyield Intermediate I-109A (1.06 g, 5.40 mmol, 42.8% yield), as a yellowoil. LC-MS: Method H, MS (ESI) m/z: 197.0 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 9.41 (d, J=2.6 Hz, 1H), 8.49 (dd, J=8.6, 2.6 Hz, 1H), 7.56 (d,J=8.6 Hz, 1H), 4.02 (s, 2H), 3.78 (s, 3H).

Intermediate I-109B: 2-(5-nitropyridin-2-yl)ethanol

This intermediate was prepared from Intermediate I-109A using ProcedureF. Intermediate I-109B was afforded in quantitative yield and wasbrought forward without purification. LC-MS: Method H, MS (ESI) m/z:169.0 (M+H)⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 9.30 (d, J=2.6 Hz, 1H), 8.51(dd, J=8.6, 2.6 Hz, 1H), 7.64-7.49 (m, 1H), 3.96 (t, J=6.3 Hz, 2H), 3.12(t, J=6.4 Hz, 2H).

Intermediate I-109C:2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-nitropyridine

Intermediate I-109B was reacted according to Procedure I using THF as asolvent to afford Intermediate I-109C (0.150 g, 0.531 mmol, 89% yield)as a yellow oil. LC-MS: Method H, MS (ESI) m/z: 283.1 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 9.27 (d, J=2.6 Hz, 1H), 8.28 (dd, J=8.6, 2.6 Hz, 1H),7.32 (d, J=8.6 Hz, 1H), 3.92 (t, J=6.2 Hz, 2H), 3.01 (t, J=6.2 Hz, 2H),0.81 (s, 9H), 0.00 (s, 6H).

Intermediate I-109

Intermediate I-109C (0.150 g, 0.531 mmol) was dissolved in ethanol (5.3ml) and Pd—C (0.113 g, 0.106 mmol, 10% by wt.) was added to the solutionfollowed by ammonium formate (0.167 g, 2.66 mmol). The reaction mixturewas allowed to stir at reflux for 3 hours and was then filtered overcelite and concentrated under reduced pressure to yield IntermediateI-109 (0.075 g, 0.297 mmol, 56% yield). LC-MS: Method H, MS (ESI) m/z:253.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=2.6 Hz, 1H), 7.02 (s,1H), 6.99-6.94 (m, 1H), 3.94 (t, J=6.7 Hz, 2H), 3.69-3.54 (m, 2H), 2.92(s, 2H), 0.89 (s, 9H), 0.00 (s, 6H).

Intermediate I-1102-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-4-amine

Intermediate I-110A: 2-((4-bromopyridin-2-yl)oxy)ethanol

This intermediate was prepared according to Procedure D fromethane-1,2-diol. Intermediate I-110A was afforded in 78% yield afterchromatography. LC-MS: Method H, MS (ESI) m/z: 219.9 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.98 (d, J=5.5 Hz, 1H), 7.09 (dd, 1.5 Hz, 1H), 7.04 (d,J=1.5 Hz, 1H), 4.51-4.47 (m, 2H), 4.01-3.87 (m, 2H), 3.16 (s, 1H).

Intermediate I-110

Intermediate I-110A was reacted according to Procedure E to afford the4-aminopyridine intermediate which was brought forward without furtherpurification. To a solution of the crude 4-aminopyridine intermediate(205 mg, 1.330 mmol) dissolved in THF (5 mL) was added DMAP (32.5 mg,0.266 mmol) and TEA (0.927 mL, 6.65 mmol) followed by TBS-Cl (1002 mg,6.65 mmol) and the mixture was allowed to stir for 18 h at roomtemperature. The mixture was then filtered through celite and thefiltrate was concentrated. The resulting residue was dissolved inmethylene chloride before being charged to a 24 g silica gel cartridgewhich was eluted with a 15 min gradient from 0-25% 2M NH₃/MeOH inmethylene chloride. The fractions containing desired product wereextracted with saturated sodium bicarbonate (3×) to remove triethylamine hydrochloride, washed with brine (1×), dried with sodium sulfate,filtered and concentrated to yield Intermediate I-110 (70 mg, 0.261mmol, 20% yield), as a clear oil. LC-MS: Method H, MS (ESI) m/z: 269.4(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.89-7.58 (m, 1H), 6.27-6.08 (m, 1H),6.02-5.63 (m, 1H), 4.28-4.18 (m, 2H), 3.91-3.80 (m, 2H), 0.82 (s, 9H),0.00 (s, 6H).

Intermediate I-111(R)-2-(2-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-4-amine,(R)-2-((1-((tert-butyldimethylsilyl)oxy)propan-2-yl)oxy)pyridin-4-amine(regioisomeric mixture)

Intermediate I-111A: (R)-1-((4-bromopyridin-2-yl)oxy)propan-2-ol,(R)-2-((4-bromopyridin-2-yl)oxy)propan-1-ol (mixture of regioisomer)

This intermediate was prepared from (R)-propane-1,2-diol using ProcedureD. Intermediate I-111A was afforded as mixture of regioisomers inquantitative yield. LC-MS: Method H, MS (ESI) m/z: 233.9 (M+H)⁺.

Intermediate I-111

Intermediate I-111A was reacted according to Procedure E to afford the4-aminopyridine intermediates as a mixture of regioisomers. To the crudemixture of 4-aminopyridine regioisomers (302 mg, 1.8 mmol) dissolved inTHF (5 mL) was added DMAP (43.9 mg, 0.359 mmol) and TEA (1.251 mL, 8.98mmol) followed by TBS-Cl (1353 mg, 8.98 mmol) and the reaction mixturewas allowed to stir at room temperature for 18 h. The reaction mixturewas then filtered through celite and the filtrate was concentrated. Theresulting residue was dissolved in methylene chloride before beingcharged to a 24 g silica gel cartridge which was eluted with a 15 mingradient from 0-25% 2M NH₃/MeOH in methylene chloride. Fractionscontaining the desired product were concentrated to yield IntermediateI-111 as a mixture (327 mg, 1.2 mmol, 65% yield). LC-MS: Method H, MS(ESI) m/z: 283.0 (M+H)⁺.

Intermediate I-1125-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-amine

Intermediate I-112A: ethyl5-((tert-butoxycarbonyl)amino)-2-methylnicotinate

Tert-butyl carbamate (605 mg, 5.16 mmol), ethyl5-bromo-2-methylnicotinate (420 mg, 1.72 mmol), xanthphos (100 mg, 0.172mmol), Pd₂(dba)₃ (158 mg, 0.172 mmol), cesium carbonate (1121 mg, 3.44mmol) and tert-butyl carbamate (605 mg, 5.16 mmol) were dissolved indioxane (10 mL) in a pressure rated vial and evacuated and backfilledwith Ar 3×. The reaction mixture was then heated at 85° C. for 18 h. Thereaction mixture was then filtered through celite and the filtrate wasconcentrated. The resulting residue was dissolved in a small amount ofmethylene chloride before being charged to a 4 g silica gel cartridgewhich was eluted with a 15 min gradient from 0-100% EtOAc in hexane.Fractions containing the desired product were concentrated to yieldIntermediate I-112A in quantitative yield. ¹H NMR (400 MHz, CDCl₃) δ8.44 (d, J=2.6 Hz, 1H), 8.32-8.24 (m, 1H), 6.49-6.31 (m, 1H), 4.31 (q,J=7.3 Hz, 2H), 1.46 (s, 9H), 1.33 (t, J=7.2 Hz, 3H).

Intermediate I-112

Intermediate I-112A (555 mg, 1.4 mmol) was dissolved in DCM (10 mL)/TFA(2.5 mL) and the solution was stirred for 30 minutes at roomtemperature. The reaction mixture was then concentrated to yield thedeprotected aminopyridine intermediate. This crude intermediate wasdissolved in THF (20 mL) at 0° C. under Ar. 1M LAH in THF (12.94 mL,12.94 mmol) was added dropwise to the reaction mixture and the reactionmixture was allowed to stir at room temperature for 1.5 hours. Thereaction mixture was then cooled to 0° C. and quenched with 0.5 mL ofwater, 1 mL of 3N NaOH and then 5 mL of water. Magnesium sulfate wasadded to the quenched mixture, which stirred for 10 minutes before beingfiltered through celite and concentrated to yield the alcoholintermediate. To the crude alcohol dissolved in DCM (10 mL) was addedimidazole (308 mg, 4.53 mmol) followed by TBS-Cl (634 mg, 4.21 mmol).The reaction mixture was stirred at room temperature for 1 hour and wasthen concentrated to dryness. The resulting residue was dissolved in asmall amount of methylene chloride before being charged to a 12 g silicagel cartridge which was eluted with a 15 min gradient from 0-100% EtOAcin hexane. Fractions containing desired product were concentrated toyield Intermediate I-112 (22 mg, 0.087 mmol, 3% yield). LC-MS: Method H,MS (ESI) m/z: 253.2 (M+H)⁺.

Intermediate I-113(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidin-5-amine

Intermediate I-113A:(R)-5-bromo-2((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy) pyrimidine

(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (189 mg, 1.429 mmol) wasreacted with 5-bromopyrimidin-2-ol (250 mg, 1.429 mmol) according to theprocedure described for Intermediate I-104C. After silica gelchromatography, Intermediate I-113A (315 mg, 1.089 mmol, 76% yield) wasyielded as a colorless oil. LC-MS: Method H, MS (ESI) m/z: 290.1 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1H), 4.54-4.46 (m, 1H), 4.46-4.40 (m,1H), 4.38-4.31 (m, 1H), 4.15 (dd, J=8.6, 6.4 Hz, 1H), 3.93 (dd, J=8.5,5.6 Hz, 1H), 1.45 (s, 3H), 1.38 (s, 3H).

Intermediate I-113B:(R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(diphenylmethylene)pyrimidin-5-amine

Intermediate I-113A ((315 mg, 1.089 mmol) was reacted according toProcedure B to afford Intermediate I-113B, (300 mg, 1.089 mmol, 71%yield). LC-MS: Method H, MS (ESI) m/z: 390.1 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.95 (s, 1H), 7.79-7.72 (m, 1H), 7.53-7.47 (m, 1H), 7.45-7.39(m, 2H), 7.38-7.31 (m, 3H), 7.16-7.09 (m, 2H), 4.50-4.42 (m, 1H),4.38-4.31 (m, 1H), 4.29-4.23 (m, 1H), 4.15-4.08 (m, 1H), 3.91 (dd,J=8.6, 5.7 Hz, 1H), 1.45-1.41 (m, 3H), 1.39-1.35 (m, 3H).

Intermediate I-113

Intermediate I-113B (300 mg, 0.770 mmol) was solvated in MeOH with 0.1%TFA (8 mL) and the solution was stirred vigorously. After 30 min ofstirring, the reaction mixture was passed through a PL-HCO₃ ion exchangecartridge and washed with MeOH to remove the TFA. The resulting solutionwas concentrated and azeotroped with toluene to afford a 1:1 mixture ofIntermediate I-113 and benzophenone (115 mg, 0.631 mmol, 82% yield). Theintermediate was brought forward without further purification. LC-MS:Method H, MS (ESI) m/z: 226.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s,1H), 4.55-4.44 (m, 1H), 4.41-4.33 (m, 1H), 4.30-4.21 (m, 1H), 4.15 (dd,J=8.6, 6.2 Hz, 1H), 3.93 (dd, J=8.5, 5.8 Hz, 1H), 1.45 (s, 3H), 1.38 (s,3H).

Intermediate I-114(S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidin-5-amine

Intermediate I-114 was prepared using the same reaction sequence asdescribed for I-113. LC-MS: Method H, MS (ESI) m/z: 226.2 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.03 (s, 1H), 4.55-4.44 (m, 1H), 4.41-4.33 (m, 1H),4.30-4.21 (m, 1H), 4.15 (dd, J=8.6, 6.2 Hz, 1H), 3.93 (dd, J=8.5, 5.8Hz, 1H), 1.45 (s, 3H), 1.38 (s, 3H).

Intermediate I-115 N2,N2-dimethylpyrimidine-2,5-diamine, 2 HCl

Intermediate I-115A:N5-(diphenylmethylene)-N2,N2-dimethylpyrimidine-2,5-diamine

5-bromo-N,N-dimethylpyrimidin-2-amine (200 mg, 1.0 mmol) was reactedaccording to Procedure B to afford Intermediate I-115A, (70 mg, 0.23mmol, 24% yield) after chromatography. LC-MS: Method H, MS (ESI) m/z:303.2 (M+H)⁺.

Intermediate I-115

Intermediate I-115A was reacted according to Procedure C to affordIntermediate I-115 in quantitative yield. This intermediate was broughtforward without further purification. LC-MS: Method H, MS (ESI) m/z:138.9 (M+H)⁺.

Intermediate I-116 N-(5-aminopyrimidin-2-yl)-N-methylmethanesulfonamide

Intermediate I-116A:N-(5-bromopyrimidin-2-yl)-N-methylmethanesulfonamide

To a solution of 5-bromo-N-methylpyrimidin-2-amine (2.55 g, 13.56 mmol)in DMF (30 mL) at 0° C. was added NaH (0.705 g, 17.63 mmol)portion-wise. The mixture was stirred for 30 min at 0° C.Methanesulfonyl chloride (1.864 g, 16.27 mmol) was then added dropwise.The mixture was warmed to room temperature and stirred for an additional2 h at room temperature. The reaction mixture was then quenched withwater (10 mL) at 0° C. and then extracted with EtOAc (3×30 mL). Thecombined organic layer was washed with brine (30 mL), dried over MgSO₄,filtered, and concentrated. This resulting residue was dissolved in asmall amount of methylene chloride before being charged to an 80 gcolumn which was eluted with 1% MeOH in DCM. Fractions containing thedesired product were concentrated to yield Intermediate I-116A (1.26 g,35% yield). LC-MS: Method H, MS (ESI) m/z: 268.0 (M+H)⁺.

Intermediate I-116

Intermediate I-116A was reacted according to Procedure B to provide tothe desired imine intermediate after silica gel chromatography. Thisimine intermediate was reacted according to Procedure C to afford thedesired product which was brought forward without further purification.LC-MS: Method H, MS (ESI) m/z: 203.0 (M+H)⁺.

Intermediate I-117 methyl 3-(5-aminopyrimidin-2-yl)propanoate

Intermediate I-117A:5-((diphenylmethylene)amino)pyrimidine-2-carbaldehyde

Intermediate I-107A (1.1 g, 3.47 mmol) was dissolved in THF (50 ml) andthe mixture was cooled to −78° C. DIBAL-H (10.40 ml, 10.40 mmol) wasadded to the mixture which was allowed to stir for 1 hour at −78° C. Thereaction mixture was then quenched with saturated Rochelle's salt at−78° C. and the resulting slurry was allowed to stir overnight under astream of Ar. The mixture was then extracted with EtOAc (3×) and thecombined organic layer was washed with brine, dried with sodium sulfate,filtered through celite and concentrated to yield Intermediate I-117A inquantitative yield. LC-MS: Method H, MS (ESI) m/z: 154.1 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.17 (s, 2H), 3.80 (s, 3H).

Intermediate I-117B: (E)-methyl3-(5-((diphenylmethylene)amino)pyrimidin-2-yl)acrylate

Methyl 2-(dimethoxyphosphoryl)acetate (0.190 g, 1.044 mmol) wasdissolved in THF (10 mL). 60% sodium hydride in mineral oil (0.042 g,1.044 mmol) was added to the solution at 0° C. and the solution wasallowed to stir at 0° C. for 20 minutes. Intermediate I-117A (0.25 g,0.870 mmol) dissolved in 2 mL of THF was then added to the reactionmixture at 0° C. which was then allowed to warm to room temperature andstir for 5 minutes. The reaction mixture was then quenched withsaturated ammonium chloride and extracted with EtOAc (3×). The combinedorganic layer was washed with brine, dried with sodium sulfate, filteredand concentrated. The resulting residue was dissolved in a small amountof methylene chloride and charged to a 24 g silica gel cartridge whichwas eluted with a 15 min gradient from 0-100% EtOAc in hexane. Fractionscontaining desired product were collected and concentrated to yieldIntermediate I-117B (250 mg, 0.728 mmol, 84% yield) as a yellow solid.LC-MS: Method H, MS (ESI) m/z: 344.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.18 (s, 2H), 7.84-7.71 (m, 3H), 7.60 (d, J=15.8 Hz, 1H), 7.55-7.29 (m,8H), 7.17-7.09 (m, 3H), 7.02 (d, J=15.6 Hz, 1H), 3.80 (s, 3H).

Intermediate I-117

Intermediate I-117B (170 mg, 0.495 mmol) was dissolved in MeOH (10mL)/water (0.5 mL). TFA (0.038 mL, 0.495 mmol) was added to the solutionwhich was allowed to stir at room temperature for 2.5 h. The reactionmixture was concentrated. The resulting free aniline intermediate wasthen dissolved in ethanol (10 mL)/ethyl acetate (10 mL) and Hunig's Base(0.432 mL, 2.473 mmol) was added to the solution. Wet Pd—C (25 mg, 0.235mmol, 10% by wt.) was then added to the reaction mixture which wasevacuated and backfilled with 1 atm of hydrogen 3×. The reaction mixturewas allowed to stir for 1 h under 1 atm of hydrogen at room temperature.The mixture was then filtered through a pad of celite, concentrated andthe resulting residue was dissolved in methylene chloride and charged toa 12 g silica gel cartridge which was eluted with a 15 min gradient from0-20% MeOH in methylene chloride. Fractions containing the desiredproduct were collected and concentrated to yield Intermediate I-117 (30mg, 0.166 mmol, 34% yield). LC-MS: Method H, MS (ESI) m/z: 182.1 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 2H), 3.70 (s, 3H), 3.60 (br. s., 2H),3.22 (t, J=7.4 Hz, 2H), 2.86 (t, J=7.4 Hz, 2H).

Intermediate I-118 methyl5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)nicotinate

Intermediate I-118 was prepared from Intermediate I-72 and methyl5-aminonicotinate according to the procedure described in the table ofcarbamate examples below. LC-MS: Method H, MS (ESI) m/z: 593.0 (M+H)⁺.

Intermediate I-1195-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine

Methyl 5-aminonicotinate (250 mg, 1.643 mmol) was dissolved in THF (20mL) at 0° C. LAH (6.57 mL, 6.57 mmol, 1 M in THF) was added dropwise tothe solution over 2 minutes. The reaction mixture was then allowed towarm to room temperature and stirred at room temperature for 1.5 hours.The reaction mixture was then quenched water at 0° C. (1 mL), followedby addition of 1M NaOH (2 mL) and an additional 4 mL of water. Thequenched reaction mixture was stirred for 10 minutes at room temperaturethen magnesium sulfate was added. The mixture was filtered throughcelite and the filtrate was concentrated to yield the intermediatealcohol. This crude alcohol intermediate was reacted according toProcedure I to yield Intermediate I-119 (251 mg, 1.05 mmol, 65% yield)after silica chromatography. LC-MS: Method H, MS (ESI) m/z: 239.2(M+H)⁺.

Intermediate I-120(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-formylpyrimidin-5-yl)carbamate

Intermediate I-86 (16 mg, 0.027 mmol) was dissolved in THF (5 mL) andcooled −78° C. DIBAL-H (0.135 mL, 0.135 mmol) was added to the reactionmixture dropwise which was then allowed to stir at −78° C. for 1 hour.The mixture was then quenched with saturated Rochelle's salt and stirredfor 30 min. at room temperature. The resulting mixture was extractedwith EtOAc (3×) and the combined organic layer was washed with brine,dried with sodium sulfate, filtered and concentrated to yieldIntermediate I-120 (5 mg, 8.89 μmol, 32.9% yield). The product wasbrought forward without further purification. LC-MS: Method H, MS (ESI)m/z: 562.9 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.92 (s, 1H), 8.99 (s, 2H),8.53-8.28 (m, 2H), 7.77-7.60 (m, 2H), 7.42 (d, J=7.7 Hz, 1H), 6.91 (s,1H), 5.17-5.05 (m, 1H), 4.66-4.46 (m, 1H), 4.13-3.83 (m, 3H), 2.56 (s,3H), 1.47-1.39 (m, 3H), 1.35-1.33 (m, 3H).

Intermediate I-1216-chloro-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate I-121A: 8-bromo-6-chloro-3-methoxyquinoline

Intermediate I-122 (2 g, 6.78 mmol), potassium carbonate (2.81 g, 20.3mmol), and methyl iodide (0.848 mL, 13.6 mmol) were dissolved in acetone(67.8 mL) and heated to 50° C. in a sealed tube. After heatingovernight, the reaction mixture was diluted with EtOAc, washed withwater, then brine, dried (Na₂SO₄), filtered, and concentrated in vacuoto give I-121A (2.04 g, 7.48 mmol) as a yellow solid: ¹H NMR (400 MHz,CDCl₃) δ 8.76 (d, J=2.6 Hz, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.70 (d, J=2.2Hz, 1H), 7.29 (d, J=2.9 Hz, 1H), 3.97 (s, 3H); LC-MS: Method H, RT=1.07min, MS (ESI) m/z: 272/274 (M+H)⁺.

Intermediate I-121

Intermediate I-121A (1 g, 3.67 mmol), bispinacolatodiboron (1.86 g, 7.34mmol), potassium acetate (0.900 g, 9.17 mmol), and PdCl₂(dppf)-CH₂Cl₂adduct (0.240 g, 0.294 mmol) were stored on HIVAC for 15 minutes thenwere dissolved in dry 1,4-dioxane (18.4 mL) and degassed for 15 minutesby bubbling with argon. The reaction mixture was heated to 130° C. inthe microwave for 40 minutes. The reaction mixture was diluted withEtOAc and washed with water then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0to 100% EtOAc in DCM, followed by 0 to 20% MeOH in DCM) to giveIntermediate I-121 (368 mg, 1.15 mmol, 31.4%) as a brown solid: LC-MS:Method H, RT=0.81 min, MS (ESI) m/z: 237.9 (boronic acid mass observed,M+H)⁺.

Intermediate I-122 8-bromo-6-chloroquinolin-3-ol, HCl

Intermediate I-122A: 3-(benzyloxy)-8-bromo-6-chloroquinoline

Intermediate I-123 (5 g, 21.32 mmol), 2-(benzyloxy)acetaldehyde (3.20 g,21.3 mmol), and sodium methoxide solution (0.5 M in MeOH, 46.9 mL, 23.5mmol) were dissolved in MeOH (42.6 mL) and heated to reflux. Afterheating overnight, the reaction mixture was diluted with saturatedNH₄Cl, partially concentrated in vacuo and diluted with EtOAc. Thelayers were separated and the organic layer was washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 330 g silica gel column, 30minute gradient from 0 to 17% EtOAc in hexanes) to give IntermediateI-122A (4.97 g, 14.3 mmol, 67%) as a yellow solid: ¹H NMR (500 MHz,CDCl₃) δ 8.85 (d, J=2.8 Hz, 1H), 7.89 (d, J=1.9 Hz, 1H), 7.69 (d, J=2.2Hz, 1H), 7.52-7.48 (m, 2H), 7.48-7.43 (m, 2H), 7.43-7.38 (m, 1H), 7.37(d, J=2.8 Hz, 1H), 5.24 (s, 2H); LC-MS: Method H, RT=1.46 min, MS (ESI)m/z: 348/350 (M+H)⁺.

Intermediate I-122

Intermediate I-122A (4.87 g, 14 mmol) and pentamethylbenzene (14.5 g, 98mmol) were dissolved in DCM (279 mL) and cooled to −78° C. Borontrichloride (1 M in heptane, 36.3 mL, 36.3 mmol) was then added and thereaction mixture was allowed to slowly warm to ambient temperature.After stirring overnight, the reaction mixture was diluted with hexanesand 1 N HCl and allowed to stir for 1 hour. The resulting solid wascollected by suction filtration, rinsing with water and hexanes to giveIntermediate I-122 (3.39 g, 11.5 mmol, 82%) as an off-white solid: ¹HNMR (400 MHz, MeOH₄) δ 8.59 (d, J=2.6 Hz, 1H), 7.84 (d, J=2.2 Hz, 1H),7.80 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.6 Hz, 1H); LC-MS: Method H, RT=0.92min, MS (ESI) m/z: 258/260 (M+H)⁺.

Intermediate I-123 2-amino-3-bromo-5-chlorobenzaldehyde

Intermediate I-123A: methyl 2-amino-3-bromo-5-chlorobenzoate

Methyl 2-amino-5-chlorobenzoate (18.1 g, 97 mmol) and NBS (17.3 g, 97mmol) were dissolved in AcOH (195 mL) and heated to 120° C. After 1.5hours, the reaction mixture was cooled to ambient temperature anddiluted with EtOAc. The reaction was then quenched with vigorousstirring with saturated NaHCO₃. The layers were separated and theorganic layer further washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate I-123A (25.7 g, 97 mmol,100%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J=2.4 Hz,1H), 7.59 (d, J=2.4 Hz, 1H), 6.36 (br. s., 2H), 3.92 (s, 3H); LC-MS:Method H, RT=1.20 min, MS (ESI) m/z: 264/266 (M+H)⁺.

Intermediate I-123B: (2-amino-3-bromo-5-chlorophenyl)methanol

Intermediate I-123A (25.7 g, 97 mmol) was dissolved in THF (324 mL).Lithium borohydride (4.23 g, 194 mmol) was added and the reactionmixture was heated to 50° C. After 2 hours, the reaction mixture wasdiluted with water and stirred for 30 minutes. All of the lithiumborohydride had not dissolved, so concentrated HCl was added carefullyto speed up the quenching process. The reaction mixture was thenextracted thrice with EtOAc. The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to giveIntermediate I-123B (23.9 g, 101 mmol, 100%) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 7.43 (d, J=2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 4.72(br. s., 2H), 4.68 (d, J=5.9 Hz, 2H), 1.63 (t, J=5.8 Hz, 1H); LC-MS:Method H, RT=1.11 min, MS (ESI) m/z: 236/238 (M+H)⁺.

Intermediate I-123

Intermediate I-123B (23.9 g, 101 mmol) was dissolved in CHCl₃ (674 mL).Manganese dioxide (17.6 g, 202 mmol) was added and the reaction mixturewas heated to 40° C. After heating for 2 days, more manganese dioxide(17.6 g, 202 mmol) was added and heating was continued. After heatingovernight, the reaction mixture was filtered through celite andconcentrated in vacuo to give Intermediate I-123 (22 g, 94 mmol, 93%) asa yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 9.79 (s, 1H), 7.64 (d, J=2.4Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 6.70 (br. s., 2H); LC-MS: Method H,RT=1.27 min, compound did not ionize.

Intermediate I-1243-methoxy-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate I-125 (183 mg, 0.726 mmol), bispinacolatodiboron (369 mg,1.45 mmol), potassium acetate (178 mg, 1.82 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (47.4 mg, 0.058 mmol) were stored on HIVAC for15 minutes then were dissolved in dry 1,4-dioxane (7.26 mL) and degassedfor 15 minutes by bubbling with argon. The reaction mixture was heatedto 130° C. in the microwave for 40 minutes. The reaction mixture wasdiluted with EtOAc and washed with water then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 24 g silica gel column, 19 minute gradientfrom 0 to 100% EtOAc in DCM then 0 to 20% MeOH in DCM) to giveIntermediate I-124 (108 mg, 0.36 mmol, 50%) as a brown solid: LC-MS:Method H, RT=0.80 min, MS (ESI) m/z: 218.0 (boronic acid observed,M+H)⁺.

Intermediate I-125 8-bromo-3-methoxy-6-methylquinoline

Intermediate I-125A: methyl 2-amino-3-bromo-5-methylbenzoate

2-Amino-3-bromo-5-methylbenzoic acid (3.8 g, 16.5 mmol) was dissolved inMeOH (33.0 mL). Thionyl chloride (3.62 mL, 49.6 mmol) was addedcarefully dropwise and the reaction mixture was heated to 65° C. Afterstirring for 8 days, the reaction mixture was concentrated in vacuo. Thecrude material was redissolved in EtOAc, washed with 1 N NaOH, water,then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to giveIntermediate I-125A (3.38 g, 13.9 mmol, 84%) as an orange oil: ¹H NMR(400 MHz, CDCl₃) δ 7.66 (d, J=1.1 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H), 6.14(br. s., 2H), 3.88 (s, 3H), 2.22 (s, 3H); LC-MS: Method H, RT=1.18 min,MS (ESI) m/z: 244/246 (M+H)⁺.

Intermediate I-125B: (2-amino-3-bromo-5-methylphenyl)methanol

Intermediate I-125A (3.38 g, 13.8 mmol) was dissolved in THF (46.2 mL).Lithium borohydride (0.603 g, 27.7 mmol) was added and the reactionmixture was heated to 50° C. After 1 hour, the reaction mixture wasdiluted with water and stirred for 30 minutes. All of the lithiumborohydride had not dissolved, so concentrated HCl was added carefullyto speed up the quenching process. The reaction mixture was thenextracted thrice with EtOAc. The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to giveIntermediate I-125B (2.85 g, 13.2 mmol, 95%) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 7.23 (d, J=1.1 Hz, 1H), 6.84 (d, J=1.3 Hz, 1H), 4.65(s, 2H), 4.53 (br. s., 2H), 2.22 (s, 3H); LC-MS: Method H, RT=1.00 min,MS (ESI) m/z: 216/218 (M+H)⁺.

Intermediate I-125C: 2-amino-3-bromo-5-methylbenzaldehyde

Intermediate I-125B (2.85 g, 13.2 mmol) was dissolved in CHCl₃ (88 mL).Manganese dioxide (6.88 g, 79 mmol) was added and the reaction mixturewas heated to 40° C. After heating overnight, the reaction mixture wasfiltered through celite and concentrated in vacuo to give IntermediateI-125C (2.72 g, 12.7 mmol, 96%) as a yellow solid: ¹H NMR (400 MHz,CDCl₃) δ 9.78 (s, 1H), 7.47 (d, J=1.5 Hz, 1H), 7.28-7.26 (m, 1H), 6.49(br. s., 2H), 2.28 (s, 3H); LC-MS: Method H, RT=1.26 min, MS (ESI) m/z:214/216 (M+H)⁺.

Intermediate I-125D: 3-(benzyloxy)-8-bromo-6-methylquinoline

Intermediate I-125C (2.72 g, 12.7 mmol), 2-(benzyloxy)acetaldehyde (1.91g, 12.7 mmol), and sodium methoxide (0.5 M in MeOH, 28.0 mL, 13.98 mmol)were dissolved in MeOH (50.8 mL) and heated to reflux. After heatingovernight, the reaction mixture was diluted with saturated NH₄Cl,partially concentrated in vacuo and diluted with EtOAc. The layers wereseparated and the organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 220 g silica gel column, 41 minute gradientfrom 0 to 40% EtOAc in hexanes) to give Intermediate I-125D (1.86 g,5.67 mmol, 45%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d,J=2.9 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.51-7.46 (m, 2H), 7.45-7.40 (m,3H), 7.39-7.33 (m, 2H), 5.20 (s, 2H), 2.49 (s, 3H); LC-MS: Method H,RT=1.22 min, MS (ESI) m/z: 328/330 (M+H)⁺.

Intermediate I-125E: 8-bromo-6-methylquinolin-3-ol

Intermediate I-125D (1.86 g, 5.67 mmol) and pentamethylbenzene (5.88 g,39.7 mmol) were dissolved in DCM (113 mL) and cooled to −78° C. Borontrichloride (1 M in heptane, 14.7 mL, 14.7 mmol) was added and thereaction mixture was allowed to warm slowly to ambient temperature.After stirring overnight, the reaction mixture was diluted with hexanesand 1 N HCl and allowed to stir for 1 hour. The aqueous layer stillcontained product by LCMS. The aqueous layer was neutralized with NaOHuntil approximately pH 7 and copious amounts of precipitates wereformed. The precipitate was collected by suction filtration to giveI-125E (829 mg, 3.48 mmol, 62%) as an off-white solid: ¹H NMR (400 MHz,MeOH₄) δ 8.50 (d, J=2.6 Hz, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.43 (d,J=1.8 Hz, 1H), 2.47 (s, 3H); LC-MS: Method H, RT=0.82 min, MS (ESI) m/z:238/240 (M+H)⁺.

Intermediate I-125

Intermediate I-125E (200 mg, 0.728 mmol), K₂CO₃ (302 mg, 2.18 mmol), andmethyl iodide (91 μl, 1.46 mmol) were dissolved in acetone (7.29 mL) andheated to 50° C. in a sealed tube. After heating overnight, the reactionmixture was diluted with EtOAc, washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate I-125(207 mg, 0.82 mmol, 100%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ8.71 (d, J=2.9 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.46 (s, 1H), 7.29 (d,J=2.9 Hz, 1H), 3.95 (s, 3H), 2.50 (s, 3H); LC-MS: Method H, RT=1.06 min,MS (ESI) m/z: 252/254 (M+H)⁺.

Intermediate I-1266-chloro-3-ethoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate I-126A: 8-bromo-6-chloro-3-ethoxyquinoline

Intermediate I-122 (300 mg, 1.02 mmol), K₂CO₃ (422 mg, 3.05 mmol), andiodoethane (163 μL, 2.03 mmol) were dissolved in Acetone (10 mL) andheated to 50° C. in a sealed tube. After heating overnight, the reactionmixture was diluted with EtOAc, washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give IntermediateI-126A (319 mg, 1.11 mmol, 100%) as a light yellow solid: ¹H NMR (400MHz, CDCl₃) δ 8.74 (d, J=2.6 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.67 (d,J=2.2 Hz, 1H), 7.28-7.24 (m, 1H), 4.17 (q, J=6.9 Hz, 2H), 1.52 (t, J=7.0Hz, 3H); LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 286/288 (M+H)⁺.

Intermediate I-126

Intermediate I-126A (319 mg, 1.11 mmol), bispinacolatodiboron (565 mg,2.23 mmol), potassium acetate (273 mg, 2.78 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (72.7 mg, 0.089 mmol) were stored on HIVAC for15 minutes then were dissolved in dry 1,4-dioxane (5.67 mL) and degassedfor 15 minutes by bubbling with argon. The reaction mixture was heatedto 130° C. in the microwave for 40 minutes. The reaction mixture wasdiluted with EtOAc and washed with water then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 80 g silica gel column, 29 minute gradientfrom 0 to 100% EtOAc in DCM, followed by 0 to 20% MeOH in DCM) to giveIntermediate I-126 (114 mg, 0.343 mmol, 31%) as a brown solid: LC-MS:Method H, RT=0.88 min, MS (ESI) m/z: 251.9 (boronic acid mass observed,M+H)⁺.

Intermediate I-1276-chloro-3-(difluoromethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate I-127A: 8-bromo-6-chloro-3-(difluoromethoxy)quinoline

Intermediate I-122 (0.5 g, 1.7 mmol) and K₂CO₃ (1.17 g, 8.48 mmol) weresuspended in DMF (17 mL) and heated to 100° C. Sodium2-chloro-2,2-difluoroacetate (1.03 g, 6.78 mmol) was then added. Afterheating for 1 hour, the reaction mixture was cooled to ambienttemperature, diluted with water, and extracted thrice with EtOAc. Thecombined organic extracts were washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 12 g silica gel column, 17 minute gradientfrom 0 to 50% EtOAc in hexanes) to give Intermediate I-127A (342 mg,1.11 mmol, 66%) as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.87(d, J=2.6 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.78(d, J=2.0 Hz, 1H), 6.88-6.49 (m, 1H); LC-MS: Method H, RT=1.09 min, MS(ESI) m/z: 308/310 (M+H)⁺.

Intermediate I-127

Intermediate I-127A (340 mg, 1.1 mmol), bispinacolatodiboron (560 mg,2.2 mmol), potassium acetate (270 mg, 2.76 mmol), and PdCl₂(dppf)-CH₂Cl₂adduct (72.0 mg, 0.088 mmol) were stored on HIVAC for 15 minutes thenwere dissolved in dry 1,4-dioxane (5.51 mL) and degassed for 15 minutesby bubbling with argon. The reaction mixture was heated to 130° C. inthe microwave for 40 minutes. The reaction mixture was diluted withEtOAc and washed with water then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 80 g silica gel column, 29 minute gradient from 0to 100% EtOAc in DCM, followed by 0 to 20% MeOH in DCM) to giveIntermediate I-127 (175 mg, 0.492 mmol, 45%) as a brown solid: LC-MS:Method H, RT=0.93 min, MS (ESI) m/z: 274.1 (boronic acid mass observed,M+H)⁺.

Intermediate I-1286-(difluoromethyl)-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate I-128A: 8-bromo-3-methoxyquinoline-6-carbaldehyde

Intermediate I-125 (152 mg, 0.602 mmol) and selenium dioxide (401 mg,3.61 mmol) were suspended in 1,4-dioxane (3.01 mL) and heated to 180° C.in the microwave for 8 hours. The reaction mixture was filtered andconcentrated in vacuo. The solids were then suspended in DCM and theinsoluble material removed by suction filtration to give IntermediateI-128A (170 mg, 0.639 mmol, 100%) as a white solid: ¹H NMR (400 MHz,CDCl₃) δ 10.15 (s, 1H), 8.93 (d, J=2.9 Hz, 1H), 8.39 (d, J=1.8 Hz, 1H),8.25 (d, J=1.5 Hz, 1H), 7.56 (d, J=2.9 Hz, 1H), 4.04 (s, 3H); LC-MS:Method H, RT=0.89 min, MS (ESI) m/z: 266/268 (M+H)⁺.

Intermediate I-128B: 8-bromo-6-(difluoromethyl)-3-methoxyquinoline

Intermediate I-128A (50 mg, 0.188 mmol) and deoxofluor (104 μl, 0.564mmol) were dissolved in DCM (940 μL). After stirring overnight, thereaction mixture was diluted carefully with water then extracted thricewith DCM. The combined organic layers were washed with saturated NaHCO₃then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 12 g silicagel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate I-128B (37 mg, 0.129 mmol, 68%) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 8.88 (d, J=2.9 Hz, 1H), 8.03 (d, J=1.5 Hz, 1H), 7.89(d, J=1.3 Hz, 1H), 7.46 (d, J=2.9 Hz, 1H), 6.96-6.64 (t, J=56 Hz, 1H),4.02 (s, 1H); LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 288/290(M+H)⁺.

Intermediate I-128

Intermediate I-128B (37 mg, 0.128 mmol), bispinacolatodiboron (65.2 mg,0.257 mmol), potassium acetate (31.5 mg, 0.321 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (8.39 mg, 10.3 μmol) were stored on HIVAC for15 minutes then were dissolved in dry 1,4-dioxane (642 μL) and degassedfor 15 minutes by bubbling with argon. The reaction mixture was heatedto 130° C. in the microwave for 40 minutes. The reaction mixture wasdiluted with EtOAc and washed with water then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate I-128. Thecrude material was used directly in the subsequent step: LC-MS: MethodH, RT=0.80 min, MS (ESI) m/z: 254.1 (boronic acid mass observed, M+H)⁺.

Intermediate I-1296-(fluoromethyl)-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate I-129A: (8-bromo-3-methoxyquinolin-6-yl)methanol

Intermediate I-128A (50 mg, 0.188 mmol) was dissolved in MeOH (1.88 mL)and cooled to 0° C. Sodium borohydride (14.2 mg, 0.376 mmol) was thenadded. After 1 hour, the reaction mixture was diluted with EtOAc, washedwith water, then brine, dried (Na₂SO₄), filtered, and concentrated invacuo to give Intermediate I-129A (38.6 mg, 0.144 mmol, 77%) as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d, J=2.9 Hz, 1H), 7.92 (d, J=1.8Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=2.9 Hz, 1H), 4.89 (d, J=5.1 Hz, 2H),4.00 (s, 3H), 1.89 (t, J=5.6 Hz, 1H); LC-MS: Method H, RT=0.73 min, MS(ESI) m/z: 268/270 (M+H)⁺.

Intermediate I-129B: 8-bromo-6-(fluoromethyl)-3-methoxyquinoline

Intermediate I-129A (38 mg, 0.142 mmol) and Deoxofluor (78 μL, 0.425mmol) were dissolved in DCM (709 μL). After stirring overnight, thereaction mixture was diluted carefully with water then extracted thricewith DCM. The combined organic layers were washed with saturated NaHCO₃then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 12 g silicagel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate I-129B (29 mg, 0.109 mmol, 77%) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 8.83 (d, J=2.9 Hz, 1H), 7.91 (s, 1H), 7.73 (s, 1H),7.41 (d, J=2.6 Hz, 1H), 5.62-5.48 (t, J=48 Hz, 2H), 4.00 (s, 3H); LC-MS:Method H, RT=0.94 min, MS (ESI) m/z: 270/272 (M+H)⁺.

Intermediate I-129

Intermediate I-129B (29 mg, 0.107 mmol), bispinacolatodiboron (54.5 mg,0.215 mmol), potassium acetate (26.3 mg, 0.268 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (7.01 mg, 8.59 μmol) were stored on HIVAC for15 minutes then were dissolved in dry 1,4-dioxane (537 μL) and degassedfor 15 minutes by bubbling with argon. The reaction mixture was heatedto 130° C. in the microwave for 40 minutes. The reaction mixture wasdiluted with EtOAc and washed with water then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate I-129, whichwas used directly for the subsequent step: LC-MS: Method H, RT=0.68 min,MS (ESI) m/z: 236.1 (boronic acid mass observed, M+H)⁺

Intermediate I-130(2R,3S)-3-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-72A (300 mg, 0.937 mmol) was dissolved in THF (18.7 mL).Phosgene solution (15% in toluene, 7.14 mL, 9.37 mmol) was then added.After stirring overnight, the reaction mixture was concentrated in vacuoand stored on HIVAC for 3 hours. The reaction mixture was dissolved inTHF (18.7 mL). 2-Methylpyrimidin-5-amine (123 mg, 1.12 mmol) andpyridine (758 μL, 9.37 mmol) were added. After 1 hour, the reactionmixture was concentrated in vacuo and purified by column chromatography(ISCO, 24 g silica gel column, 19 minute gradient from 0 to 100% EtOAcin hexanes) to give Intermediate I-130 (327 mg, 0.796 mmol, 85%) as awhite solid: ¹H NMR (400 MHz, CDCl₃) δ 8.72 (br. s., 2H), 7.66 (d,J=11.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 6.55 (br. s., 1H), 5.14 (dd,J=6.5, 3.0 Hz, 1H), 4.60-4.49 (m, 1H), 2.71 (s, 3H), 1.44 (d, J=6.6 Hz,3H), 1.40 (d, J=6.4 Hz, 3H); LC-MS: Method H, RT=0.95 min, MS (ESI) m/z:411.0 (M+H)⁺.

Intermediate I-131(R)-1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol

Intermediate I-131A: 6-fluoro-5-methoxythiazolo[5,4-b]pyridin-2-amine

Potassium thiocyanate (0.738 g, 7.59 mmol) was dissolved in acetic acid(5 mL) and cooled to 0° C. 5-fluoro-6-methoxypyridin-3-amine (1.079 g,7.59 mmol) was dissolved in acetic acid (1.667 mL) and added dropwise.Bromine (0.782 mL, 15.18 mmol) was dissolved in acetic acid (1.667 mL)and added dropwise to the reaction. The reaction mixture was allowed towarm to room temperature and stir overnight. The reaction mixture wasconcentrated under reduced pressure. The resultant residue was dilutedwith water and neutralized with 1 N NaOH. The aqueous solution wasextracted with EtOAc×3. The combined organic layer was washed withbrine, dried with sodium sulfate, and concentrated under reducedpressure to yield Intermediate I-131A (1.496 g, 7.51 mmol, 99% yield).¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, J=10.6 Hz, 1H), 5.14 (br. s., 2H),4.03 (s, 3H). LC-MS: method H, RT=0.65 min, MS (ESI) m/z: 200.0 (M+H)⁺.

Intermediate I-131B: 2-amino-6-fluorothiazolo[5,4-b]pyridin-5-ol,2hydrobromide

Intermediate I-131A (0.500 g, 2.510 mmol) was dissolved in a solution ofHBr in acetic acid (1.704 mL, 15.06 mmol, 33% by wt.) and the reactionmixture was stirred at 130° C. for 3h. The reaction mixture wasconcentrated under reduced pressure to yield Intermediate I-131B (0.88g, 2.54 mmol, 101% yield) as a tan solid. ¹H NMR (400 MHz, MeOH₄) δ 7.66(d, J=9.7 Hz, 1H) LC-MS: method H, RT=0.45 min, MS (ESI) m/z: 186.1(M+H)⁺.

Intermediate I-131C(R)-1-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol

To a solution of Intermediate I-131B (1.00 g, 2.88 mmol) intetrahydrofuran (23.05 ml) was added (R)-4-methyl-1,3,2-dioxathiolane2,2-dioxide (0.478 g, 3.46 mmol) followed by potassium carbonate (1.195g, 8.65 mmol). The reaction mixture was stirred vigorously at 60° C. for3h then at room temperature for 48 hours. Sulfuric acid (0.768 ml, 14.41mmol) followed by water (0.156 ml, 8.65 mmol) were added slowly to thereaction. The reaction mixture was allowed to stir at room temperaturefor 1 h. The reaction mixture was diluted with 1 N NaOH and EtOAc. Thelayers were separated and the organic layer was washed with brine, driedwith sodium sulfate, and concentrated under reduced pressure to yieldIntermediate I-131C (0.284 g, 1.167 mmol, 40.5% yield) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J=10.6 Hz, 1H), 5.09 (br. s.,2H), 4.40 (d, J=7.9 Hz, 1H), 4.23 (d, J=6.6 Hz, 2H), 2.58 (d, J=2.9 Hz,1H), 1.30 (d, J=5.9 Hz, 3H). LC-MS: method H, RT=0.59 min, MS (ESI) m/z:244.1 (M+H)⁺.

Intermediate I-131

Copper(II) chloride (0.658 g, 4.89 mmol) and t-butyl nitrite (0.582 ml,4.89 mmol) were dissolved in MeCN (11.51 ml) and allowed to stir 10minutes. Intermediate I-131C (0.700 g, 2.88 mmol) was dissolved in MeCN(17.27 ml) and the copper solution was added. The reaction mixture wasstirred for 2.5 hours at 60° C. The reaction mixture was diluted withEtOAc, then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.Purified on ISCO using a 12 g column with 0-100% gradient of EtOAc inhexanes to Intermediate I-131 (0.698 g, 2.66 mmol, 92% yield). ¹H NMR(400 MHz, CDCl₃) δ 7.79 (d, J=9.9 Hz, 1H), 4.45-4.34 (m, 1H), 4.26-4.19(m, 2H), 3.86-3.71 (m, 1H), 2.25 (d, J=3.5 Hz, 1H), 1.39-1.24 (m, 3H).LC-MS: method H, RT=0.88 min, MS (ESI) m/z: 263.0 (M+H)⁺.

Intermediate I-132(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl carbonochloridate

Intermediate I-132A:(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol

Intermediate I-9 (0.343 g, 1.142 mmol) and Intermediate I-131 (0.300 g,1.142 mmol) were dissolved in DMF (11.42 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(0.056 g, 0.069 mmol) was added, and the reaction degassed by bubblingwith argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.381 ml, 1.142mmol) was added and the reaction degassed for 5 minutes, then sealed andheated to 90° C. in the microwave for 30 minutes. The reaction mixturewas purified on ISCO using a 24 g column eluting with 0-100% EtOAc inhexanes to yield Intermediate I-132A (0.223 g, 0.557 mmol, 48.8% yield)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J=12.5 Hz, 1H),8.01 (d, J=10.1 Hz, 1H), 7.78 (br. s., 1H), 7.33-7.28 (m, 1H), 4.55 (d,J=11.2 Hz, 1H), 4.38 (br. s., 2H), 4.13 (s, 4H), 2.65 (br. s., 3H), 1.35(d, J=5.9 Hz, 3H). LC-MS: method H, RT=1.25 min, MS (ESI) m/z: 401.1(M+H)⁺.

Intermediate I-132

To a solution of(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol(0.098 g, 0.245 mmol) in THF (3 mL) at room temperature was added 15%phosgene in toluene (0.863 mL, 1.224 mmol) and the mixture was stirredat room temperature for 1 h. Solvent was completely removed and thesample was under vacuum overnight to give Intermediate I-132 (0.113 g,0.244 mmol, 100% yield) as a yellow solid. This intermediate was usedwithout further purification in the next step. LC-MS: method H, RT=1.37min, MS (ESI) m/z: 463.0 (M+H)⁺.

Intermediate I-133(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol

Intermediate I-133A:(2R,3S)-3-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-ol

To a solution of Intermediate I-131B (150 mg, 0.432 mmol) in DMF (1729μl) was added (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (79mg, 0.519 mmol) followed by potassium carbonate (179 mg, 1.297 mmol).The reaction mixture was stirred vigorously at 60° C. for 3h and thenallowed to stir at room temperature for 48 h. The reaction mixture wasthen diluted with EtOAc and filtered. The resulting solution wasconcentrated under reduced pressure to yield a dark oil. This residuewas dissolved in THF (1729 μl) and sulfuric acid (69.1 μl, 1.297 mmol)followed by water (23.36 μl, 1.297 mmol). This reaction mixture wasallowed to stir at room temperature for 1 hour before being diluted with1 N NaOH and EtOAc. The layers were separated and the organic layer waswashed with brine, dried with sodium sulfate, and concentrated underreduced pressure to yield Intermediate I-133A (0.11 g, 0.428 mmol, 99%yield) as a yellow solid. ¹H NMR (400 MHz, MeOH₄) δ 7.42 (d, J=11.0 Hz,1H), 5.12-5.02 (m, 1H), 3.96-3.88 (m, 1H), 1.33 (d, J=6.4 Hz, 3H), 1.24(d, J=6.6 Hz, 3H). LC-MS: method H, RT=0.63 min, MS (ESI) m/z: 258.0(M+H)⁺.

Intermediate I-133

Copper(II) chloride (0.588 g, 4.37 mmol) and t-butyl nitrite (0.589 ml,4.96 mmol) were dissolved in MeCN (11.66 ml) and allowed to stir 10minutes. Intermediate I-133A (0.750 g, 2.92 mmol) was dissolved in MeCN(17.49 ml) and the copper solution was added. The reaction mixture wasstirred for 1.5h at 60° C. The reaction mixture was diluted with EtOAc,then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.Purified on ISCO using a 40 g column with 0-100% gradient of EtOAc inhexanes to yield Intermediate I-133 (0.722 g, 2.61 mmol, 90% yield). ¹HNMR (400 MHz, CDCl₃) δ 7.87 (d, J=9.9 Hz, 1H), 5.31 (dd, J=6.4, 3.1 Hz,1H), 4.12 (ddd, J=6.4, 4.7, 3.2 Hz, 1H), 2.14 (d, J=4.6 Hz, 1H), 1.42(d, J=6.4 Hz, 3H), 1.31 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=0.95, MS(ESI) m/z: 277.1 (M+H)⁺.

Intermediate I-134(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ylcarbonochloridate

Intermediate I-134A:(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol

Intermediate I-9 (0.067 g, 0.224 mmol) and Intermediate I-133 (0.062 g,0.224 mmol) were dissolved in DMF (2.241 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(10.98 mg, 0.013 mmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.075 ml, 0.224mmol) was added and the reaction degassed for 5 minutes, then sealed andheated to 90° C. in the microwave for 30 minutes. Purified on ISCO usinga 40 g column eluting with 0-100% EtOAc in hexanes to yield IntermediateI-134A (0.090 g, 0.219 mmol, 95%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 8.57 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.99 (d, J=10.1 Hz, 1H),7.77 (s, 1H), 5.37 (dd, J=6.4, 2.9 Hz, 1H), 4.13 (s, 3H), 2.65 (s, 3H),2.46 (d, J=4.8 Hz, 1H), 1.43 (d, J=6.4 Hz, 3H), 1.39 (d, J=6.4 Hz, 1H),1.30 (d, J=6.6 Hz, 5H). LC-MS: method H, RT=1.24 min, MS (ESI) m/z:415.1 (M+H)⁺.

Intermediate I-134

To a solution of Intermediate I-134A (0.045 g, 0.109 mmol) in THF (3 mL)at room temperature was added 15% phosgene solution in toluene (0.383mL, 0.543 mmol) and the mixture was stirred room temperature overnight.Solvent was completely removed to yield Intermediate I-134 (0.052 g,0.098 mmol, 90% yield) as a yellow solid. Used without furtherpurification in the next step. LC-MS: method H, RT=1.46 min, MS (ESI)m/z: 477.0 (M+H)⁺.

Intermediate I-135(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-135A:(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-ylcarbonochloridate

To a solution of Intermediate I-133 (0.030 g, 0.108 mmol) in THF (3 mL)at room temperature was added 15% phosgene solution in toluene (0.382mL, 0.542 mmol), and the mixture was stirred at room temperatureovernight. Solvent was completely removed to give Intermediate I-135A(0.035 g, 0.103 mmol, 95% yield) as a yellow solid. Used without furtherpurification in the next step. LC-MS: method H, RT=1.46 min, MS (ESI)m/z: 340.0 (M+H)⁺.

Intermediate I-135

2-Methylpyrimidin-5-amine (0.023 g, 0.206 mmol) and pyridine (0.083 mL,1.032 mmol) were dissolved in DCM (2 mL) To this solution was addedIntermediate I-135A (0.035 g, 0.103 mmol) as a solution in DCM (1 mL).The reaction mixture was allowed to stir for 1h. The reaction mixturewas concentrated under reduced pressure to yield Intermediate I-135(0.040 g, 0.097 mmol, 94%). LC-MS: method H, RT=1.09 min, MS (ESI) m/z:412.0 (M+H)⁺.

Intermediate I-1366-fluoro-3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate I-136A: (2-amino-3-bromo-5-fluorophenyl)methanol

Methyl 2-amino-3-bromo-5-fluorobenzoate (0.910 g, 3.67 mmol) wasdissolved in THF (12.23 ml). LiBH₄ (0.160 g, 7.34 mmol) was added andthe reaction mixture was heated to 50° C. for 2 hours. The reactionmixture was diluted with water and stirred for 30 minutes. The reactionmixture was then extracted thrice with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to yield Intermediate I-136A (0.799 g, 3.63 mmol,99% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.20 (dd, J=7.7,2.9 Hz, 1H), 6.86 (dd, J=8.4, 2.9 Hz, 1H), 4.68 (s, 2H), 4.52 (d, J=12.8Hz, 2H), 1.89-1.69 (m, 1H). LC-MS: method H, RT=0.94 min, MS (ESI) m/z:219.9 (M+H)⁺.

Intermediate I-136B: 2-amino-3-bromo-5-fluorobenzaldehyde

Intermediate I-136A (0.799 g, 3.63 mmol) was dissolved in CHCl₃ (24.21ml). Manganese dioxide (1.263 g, 14.52 mmol) was added and the reactionmixture was heated to 40° C. overnight. The reaction mixture wasfiltered through celite and concentrated in vacuo to yield IntermediateI-136B (0.750 g, 3.44 mmol, 95%). ¹H NMR (400 MHz, CDCl₃) δ 9.80 (s,1H), 7.48 (dd, J=7.5, 2.9 Hz, 1H), 7.25 (dd, J=7.9, 2.9 Hz, 1H), 6.55(br. s., 2H).

Intermediate I-136C: 3-(benzyloxy)-8-bromo-6-fluoroquinoline

Intermediate I-136B (0.800 g, 3.67 mmol), 2-(benzyloxy)acetaldehyde(0.551 g, 3.67 mmol), and sodium methoxide (8.07 ml, 4.04 mmol) weredissolved in MeOH (7.34 ml) and heated to reflux overnight. The reactionmixture was diluted with saturated NH₄Cl, partially concentrated invacuo and diluted with EtOAc. The layers were separated and the organiclayer was washed with brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. Purified on ISCO using 80 g column eluting with 0-60% gradientof EtOAc in hexanes to yield Intermediate I-136C (0.363 g, 1.093 mmol,30%). ¹H NMR (500 MHz, CDCl₃) δ 8.83 (d, J=2.5 Hz, 1H), 7.72 (dd, J=8.1,2.6 Hz, 1H), 7.52-7.49 (m, 2H), 7.45 (t, J=7.3 Hz, 2H), 7.41 (d, J=2.8Hz, 2H), 7.34 (dd, J=8.7, 2.6 Hz, 1H), 5.24 (s, 2H). LC-MS: method H,RT=1.38 min, MS (ESI) m/z: 331.9 (M+H)⁺.

Intermediate I-136D: 8-bromo-6-fluoroquinolin-3-ol

Intermediate I-136C (0.363 g, 1.093 mmol) and pentamethylbenzene (1.134g, 7.65 mmol) were dissolved in DCM (21.86 ml) and cooled to −78° C.Boron trichloride (1 M in heptane) (2.84 ml, 2.84 mmol) was added andthe reaction mixture was allowed to warm to room temperature overnight.The reaction mixture was diluted with hexanes and 1 N HCl and allowed tostir for 1 hour. The resulting solid was collected by suctionfiltration, washing with water and hexanes to yield Intermediate I-136D(0.176 g, 0.727 mmol, 66.5% yield): ¹H NMR (400 MHz, MeOH₄) δ 8.53 (d,J=2.9 Hz, 1H), 7.68 (dd, J=8.4, 2.6 Hz, 1H), 7.49-7.37 (m, 2H). LC-MS:method H, RT=1.12 min, MS (ESI) m/z: 241.9 (M+H)⁺.

Intermediate I-136E: 8-bromo-6-fluoro-3-methoxyquinoline

Intermediate I-136D (0.095 g, 0.341 mmol), K₂CO₃ (0.141 g, 1.023 mmol),and methyl iodide (0.043 ml, 0.682 mmol) were dissolved in acetone (3.41ml) and heated to 50° C. in a sealed tube overnight. The reactionmixture was diluted with EtOAc, washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to yield IntermediateI-136E (0.060 g, 0.234 mmol, 68.7% yield). ¹H NMR (400 MHz, CDCl₃) δ8.76 (dd, J=2.8, 0.6 Hz, 1H), 7.72 (dd, J=8.0, 2.8 Hz, 1H), 7.37 (dd,J=8.8, 2.6 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H), 4.00 (s, 3H). LC-MS: methodH, RT=1.31 min, MS (ESI) m/z: 255.8 (M+H)⁺.

Intermediate I-136

Intermediate I-136E (0.087 g, 0.340 mmol), BISPIN (0.173 g, 0.679 mmol),potassium acetate (0.083 g, 0.849 mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct(0.022 g, 0.027 mmol) were stored on HIVAC for 15 minutes then weredissolved in 1,4-dioxane (3 ml) and degassed for 15 minutes by bubblingwith argon. The reaction mixture was heated to 130° C. in the microwavefor 40 minutes. The reaction mixture was diluted with EtOAc and washedwith water then brine, dried (Na₂SO₄), filtered, and concentrated invacuo to yield Intermediate I-136 (0.103 g, 0.170 mmol, 50%). Thismaterial was dissolved in DMF to make a stock solution of 10 mg per mLand used without further purification. LC-MS: method H, RT=1.10 min, MS(ESI) m/z: 221.9 (M+H)⁺. See the mass of the boronic acid in the LC/MS.

Intermediate I-137(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-yl)carbamate

Intermediate I-137A:(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-ylcarbonochloridate

To a solution of Intermediate I-133 (0.100 g, 0.361 mmol) in THF (5 mL)at room temperature was added 15% phosgene solution in toluene (1.274mL, 1.807 mmol) and the mixture was stirred at room temperatureovernight. Solvent was completely removed to give Intermediate I-137A(0.125 g, 0.369 mmol, 102% yield) as a yellow solid. LC-MS: method H,RT=1.20 min, MS (ESI) m/z: 338.9 (M+H)⁺.

Intermediate I-137

2-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)pyrimidin-5-amine (0.199 g,0.737 mmol) and pyridine (0.298 mL, 3.69 mmol) were dissolved in DCM (2mL) To this solution was added Intermediate I-137A (0.125 g, 0.369 mmol)as a solution in DCM (1 mL). The reaction mixture was allowed to stirfor 1 h. The reaction mixture was concentrated under reduced pressure toyield Intermediate I-137 (0.130 g, 0.227 mmol, 62%). ¹H NMR (400 MHz,CDCl₃) δ 8.48 (br. s., 2H), 7.76 (d, J=9.7 Hz, 1H), 5.45 (dd, J=6.6, 2.9Hz, 1H), 5.12 (dd, J=6.6, 2.9 Hz, 1H), 4.33 (t, J=5.5 Hz, 2H), 3.90 (t,J=5.4 Hz, 2H), 1.34 (d, J=6.6 Hz, 6H), 0.81 (s, 9H), 0.00 (s, 6H).LC-MS: method H, RT=1.20 min, MS (ESI) m/z: 572.1 (M+H)⁺.

Intermediate I-138(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ylcarbonochloridate

Intermediate I-138A: 2-amino-7-methylthiazolo[5,4-b]pyridin-5-ol,2hydrobromide

Intermediate I-16B (0.500 g, 2.56 mmol) was dissolved in HBr in aceticacid (1.738 mL, 15.37 mmol, 33% by wt.), and the reaction mixture wasstirred at 130° C. for 3h. The reaction mixture was concentrated underreduced pressure to yield Intermediate I-138A (0.636, 1.854 mmol, 72.4%yield) as a tan solid. ¹H NMR (400 MHz, CDCl₃) δ 6.66 (d, J=0.9 Hz, 1H),2.48 (d, J=0.7 Hz, 3H). LC-MS: method H, RT=0.46 min, MS (ESI) m/z:182.1 (M+H)⁺.

Intermediate I-138B:(R)-5-(2-((tert-butyldiphenylsilyl)oxy)propoxy)-7-methylthiazolo[5,4-b]pyridin-2-amine

Intermediate I-138A (0.500 g, 1.458 mmol) was dissolved in DMF (14.58ml) and Cs₂CO₃ (2.85 g, 8.75 mmol) was added followed by(R)-tert-Butyl((1-iodopropan-2-yl)oxy)diphenylsilane (0.619 g, 1.458mmol). The reaction mixture was stirred at room temperature for 3 h. Thereaction mixture was then heated to 40° C. and allow to stir overnight.The reaction mixture was diluted with water and EtOAc. The layers wereseparated and the organic layer was washed with brine, dried with sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified on ISCO using 40 g column eluting with 0-100% EtOAc inhexanes to yield Intermediate I-138B (0.324 g, 0.678 mmol, 46.5% yield)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (ddd, J=8.0, 4.1, 1.5Hz, 4H), 7.42-7.28 (m, 6H), 6.32 (d, J=0.7 Hz, 1H), 4.97 (s, 2H),4.26-4.18 (m, 2H), 4.16-4.09 (m, 5H), 2.45 (d, J=0.7 Hz, 3H), 1.15 (d,J=6.2 Hz, 3H), 1.06 (s, 9H). LC-MS: method H, RT=1.24 min, MS (ESI) m/z:478.3 (M+H)⁺.

Intermediate I-138C(R)-5-(2-((tert-butyldiphenylsilyl)oxy)propoxy)-2-chloro-7-methylthiazolo[5,4-b]pyridine

Copper(II) chloride (0.155 g, 1.153 mmol) and t-butyl nitrite (0.137 ml,1.153 mmol) were dissolved in MeCN (2.71 ml) and allowed to stir 10minutes. Intermediate I-138B (0.324 g, 0.678 mmol) was dissolved in MeCN(4.07 ml) and the copper solution was added. The reaction mixture wasstirred for 2.5h at 60° C. The reaction mixture was diluted with EtOAc,washed with 1 N HCl, saturated NaHCO₃, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purified on ISCO using a 24 gcolumn with 0-100% gradient of EtOAc in hexanes to yield IntermediateI-138C (0.222 g, 0.447 mmol, 65.8% yield) as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 7.71-7.64 (m, 4H), 7.44-7.28 (m, 6H), 6.42 (s, 1H),4.34-4.09 (m, 3H), 2.56 (d, J=0.7 Hz, 3H), 1.18 (d, J=5.9 Hz, 3H), 1.06(s, 9H). LC-MS: method H, RT=1.71 min, MS (ESI) m/z: 497.2 (M+H)⁺.

Intermediate I-138D(R)-5-(2-((tert-butyldiphenylsilyl)oxy)propoxy)-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine

Intermediate I-9 (0.052 g, 0.173 mmol) and Intermediate I-138C (0.086 g,0.173 mmol) were dissolved in DMF (1.730 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(8.48 mg, 10.38 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100 ml, 0.300mmol) was added and the reaction degassed for 5 minutes, then sealed andheated to 90° C. in the microwave for 30 minutes. The reaction mixturewas filtered and purified on ISCO using 0-100% EtOAc in hexanes on a 24g column to yield Intermediate I-138D (0.055 g, 0.087 mmol, 50.1% yield)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J=2.0 Hz, 1H),8.54 (s, 1H), 7.71-7.69 (m, 4H), 7.41-7.30 (m, 7H), 6.47 (d, J=0.9 Hz,1H), 4.40-4.24 (m, 4H), 4.12 (s, 3H), 2.74 (d, J=0.9 Hz, 3H), 2.66 (s,3H), 1.19 (d, J=5.9 Hz, 3H), 1.08 (s, 9H). LC-MS: method H, RT=1.15 min,Compound does not ionize.

Intermediate I-138E(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol

Intermediate I-138D (0.055 g, 0.087 mmol) was dissolved in THF (0.866ml) and TBAF (0.104 ml, 0.104 mmol) was added. The reaction mixture wasallowed to stir at room temperature for 1h and concentrated underreduced pressure. Purified on ISCO using 0-100% EtOAc in hexanesgradient on a 12 g column to yield Intermediate I-138E (0.027 g, 0.068mmol, 79% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d,J=1.8 Hz, 1H), 8.54 (s, 1H), 7.75 (s, 1H), 6.75 (d, J=0.9 Hz, 1H),4.56-4.19 (m, 4H), 4.12 (s, 3H), 3.49 (d, J=5.5 Hz, 1H), 2.95 (s, 1H),2.80 (d, J=0.9 Hz, 3H), 2.66 (s, 3H), 1.31 (d, J=6.2 Hz, 3H). LC-MS:method H, RT=1.26 min, MS (ESI) m/z: 397.2 (M+H)⁺.

Intermediate I-138

To a solution of Intermediate I-138E (0.027 g, 0.068 mmol) in THF (3 mL)at room temperature was added 15% phosgene solution in toluene (0.240mL, 0.341 mmol) and the mixture was stirred at room temperature for 1 h.Solvent was completely removed and the sample was under vacuum overnightto give Intermediate I-138 (0.030 g, 0.065 mmol, 96% yield) as a yellowsolid. Used without any purification. LC-MS: method H, RT=1.43 min, MS(ESI) m/z: 459.1 (M+H)⁺.

Intermediate I-139(R)-1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-139A(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ylcarbonochloridate

To a solution of Intermediate I-131 (0.030 g, 0.114 mmol) in THF (3 mL)at room temperature was added 15% phosgene solution in toluene (0.403mL, 0.571 mmol), and the mixture was stirred at room temperatureovernight. Solvent was completely removed to give Intermediate I-139A(0.035 g, 0.108 mmol, 95% yield) as a yellow solid. Used without furtherpurification in the next step. LC-MS: method H, RT=1.22 min, MS (ESI)m/z: 325.0 (M+H)⁺.

Intermediate I-139

2-Methylpyrimidin-5-amine (0.023 g, 0.215 mmol) and pyridine (0.083 mL,1.032 mmol) were dissolved in DCM (2 mL) To this solution was addedIntermediate I-139A (0.035 g, 0.108 mmol) as a solution in DCM (1 mL).The reaction mixture was allowed to stir for 1h. The reaction mixturewas concentrated under reduced pressure to yield Intermediate I-139(0.038 g, 0.096 mmol, 89%). LC-MS: method H, RT=1.04 min, MS (ESI) m/z:398.0 (M+H)⁺.

Intermediate I-140(3-Methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-6-yl)methanol

Intermediate I-140A: 8-Bromo-3-methoxyquinoline-6-carbaldehyde

A mixture of Intermediate I-125 (0.050 g, 0.198 mmol) and seleniumdioxide (0.132 g, 1.190 mmol) in dioxane (3.0 mL) was heated in amicrowave at 180° C. for 9 hours. The insoluble material was removed byfiltration and washed with EtOAc. The crude product was purified byflash chromatography (loading in chloroform, 0% to 100% EtOAc in hexaneusing a 12 g silica gel cartridge). The desired fractions were combinedand concentrated to yield Intermediate I-140A (0.051 g, 0.163 mmol, 82%yield) as a white solid. Contains 15% starting material. Will be usedwithout further purification. LC-MS: method H, RT=0.83 min, MS (ESI)m/z: 267.9 (M+H)⁺.

Intermediate I-140B: (8-Bromo-3-methoxyquinolin-6-yl)methanol

Intermediate I-140A (0.0502 g, 0.189 mmol) was dissolved in THF (1.887ml) and sodium borohydride (7.14 mg, 0.189 mmol) was added in oneportion. The reaction mixture was allowed to stir at room temperaturefor 3h. The reaction mixture was diluted with water and EtOAc. Thelayers were separated and the organic layer was washed with water,washed with brine, dried with sodium sulfate, and concentrated underreduced pressure to yield Intermediate I-140B (0.048 g, 0.179 mmol, 95%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d, J=2.9 Hz,1H), 7.92 (d, J=1.8 Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=2.9 Hz, 1H), 4.89(d, J=5.1 Hz, 2H), 4.00 (s, 3H), 1.91 (s, 1H). LC-MS: method H, RT=0.69min, MS (ESI) m/z: 269.9 (M+H)⁺.

Intermediate I-140

Intermediate I-140B (0.0524 g, 0.195 mmol), BISPIN (0.099 g, 0.391mmol), potassium acetate (0.048 g, 0.489 mmol), and PdCl₂(dppf)-CH₂Cl₂adduct (0.013 g, 0.016 mmol) were stored on HIVAC for 15 minutes thenwere dissolved in 1,4-dioxane (3 ml) (sure sealed bottle) and degassedfor 15 minutes by bubbling with argon. The reaction mixture was heatedto 130° C. in the microwave for 40 minutes (fixed hold time off). Thereaction mixture was diluted with EtOAc and washed with water thenbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The residuewas dissolved in dioxanes to provide a 10 mg/mL stock solution of theabove boronic ester. Used without further purification. See mass ofboronic acid in the LC/MS LC-MS: method H, RT=0.50 min, MS (ESI) m/z:234.0 (M+H)⁺.

Intermediate I-141 Methyl5-(((((2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate

Intermediate I-141A:(2R,3S)-3-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) butan-2-ylcarbonochloridate

To a solution of Intermediate I-133 (0.058 g, 0.210 mmol) in THF (5 mL)at room temperature was added 15% phosgene in toluene (0.739 mL, 1.048mmol) and the mixture was stirred at room temperature overnight. Thesolvent was completely removed to give Intermediate I-141A (0.071 g,0.209 mmol, 100% yield) as a yellow solid. LC-MS: method H, RT=1.22 min,MS (ESI) m/z: 339.1 (M+H)⁺.

Intermediate I-141

Methyl 5-aminopyrimidine-2-carboxylate (0.065 g, 0.425 mmol) andpyridine (0.172 mL, 2.123 mmol) were dissolved in DCM (2 mL). To thissolution was added Intermediate I-141A (0.072 g, 0.212 mmol) as asolution in DCM (1 mL). The reaction mixture was allowed to stir for 1h.The reaction mixture was concentrated under reduced pressure. Purifiedon ISCO using 0-100% EtOAc in hexanes to yield Intermediate I-141 (0.066g, 0.145 mmol, 68.2% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ9.04 (s, 2H), 7.87 (d, J=9.7 Hz, 1H), 6.94 (s, 1H), 5.56 (dd, J=6.5, 2.8Hz, 1H), 5.38-5.17 (m, 1H), 4.09 (s, 3H), 1.47 (d, J=6.4 Hz, 6H). LC-MS:method H, RT=0.93 min, MS (ESI) m/z: 456.0 (M+H)⁺.

Intermediate I-142 (R)-methyl5-((((1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate

Intermediate I-142A:(R)-1-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy) propan-2-ylcarbonochloridate

To a solution of Intermediate I-131 (0.058 g, 0.210 mmol) in THF (5 mL)at room temperature was added 15% phosgene in toluene (0.739 mL, 1.048mmol) and the mixture was stirred at room temperature overnight. Thesolvent was completely removed to give Intermediate I-142A (0.072 g,0.221 mmol, 100% yield) as a yellow solid. LC-MS: method H, RT=1.17 min,MS (ESI) m/z: 325.1 (M+H)⁺.

Intermediate I-142

Methyl 5-aminopyrimidine-2-carboxylate (0.068 g, 0.443 mmol) andpyridine (0.179 mL, 2.214 mmol) were dissolved in DCM (2 mL). To thissolution was added Intermediate I-142A (0.072 g, 0.221 mmol) as asolution in DCM (1 mL). The reaction mixture was allowed to stir for 1h. The reaction mixture was concentrated under reduced pressure.Purified on ISCO using 0-100% EtOAc in hexanes to yield I-142 (0.87 g,0.197 mmol, 89% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.06(s, 2H), 7.89 (d, J=9.9 Hz, 1H), 6.98 (s, 1H), 5.42 (d, J=3.3 Hz, 1H),4.72 (dd, J=11.9, 3.1 Hz, 1H), 4.48 (dd, J=11.9, 6.6 Hz, 1H), 4.09 (s,3H), 1.51 (d, J=6.6 Hz, 3H). LC-MS: method H, RT=0.88 min, MS (ESI) m/z:442.0 (M+H)⁺.

Intermediate I-143(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ylcarbonochloridate

Intermediate I-143A:(2R,3S)-3-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol

To a solution of Intermediate I-44 (0.200 g, 0.708 mmol) in THF (2.83ml) was added (4R,5R)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide(0.140 g, 0.920 mmol) followed by potassium carbonate (0.147 g, 1.062mmol). The reaction vial was sealed and heated to 65° C. overnight. Thecrude mixture was cooled to 0° C. and concentrated sulfuric acid (0.113ml, 2.124 mmol) was added followed by water (0.064 ml, 3.54 mmol). Thereaction mixture was allowed to thaw to room temperature, and stirredfor 20 min. The reaction mixture was quenched with 20 mL 1.5 M K₂HPO₄,extracted with 100 mL EtOAc, washed with brine, dried over MgSO₄,filtered and concentrated to afford a beige solid that was dry loadedonto celite and purified by ISCO (40 g, 0-50% DCM/EtOAc) to affordIntermediate I-143A (0.145 g, 0.409 mmol, 57.8% yield) as an off whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J=7.0 Hz, 1H), 4.38 (dd,J=6.3, 3.4 Hz, 1H), 4.16-4.03 (m, 1H), 2.01 (d, J=4.8 Hz, 1H), 1.37 (d,J=6.4 Hz, 3H), 1.31 (d, J=6.6 Hz, 3H). LC-MS: method H, RT=0.82 min, MS(ESI) m/z: 353.9 (M+H)⁺.

Intermediate I-143B:(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol

Intermediate I-121 (149 mg, 0.467 mmol), Intermediate I-143A (145 mg,0.467 mmol) and PdCl₂(dppf) (20.52 mg, 0.028 mmol) were dissolved indioxane (8.523 mL) and Na₂CO₃ (2.104 mL, 4.21 mmol, 2 M) and heated to100° C. in an oil bath for 1 hour. The reaction mixture was cooled toambient temperature, diluted with EtOAc, washed with water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. Purified on ISCOusing 0-100% EtOAc in DCM on a 24 g column to yield Intermediate I-143B(0.022 g, 0.047 mmol, 10.07% yield): LC-MS: method H, RT=1.40 min, MS(ESI) m/z: 466.8 (M+H)⁺.

Intermediate I-143

To a solution of Intermediate I-143B (0.022 g, 0.047 mmol) in THF (5 mL)at room temperature was added 15% phosgene in toluene (0.166 mL, 0.235mmol) and the mixture was stirred at room temperature overnight. Solventwas completely removed to give Intermediate I-143 (0.025 g, 0.047 mmol,100% yield) as a yellow solid. LC-MS: method H, RT=1.41 min, MS (ESI)m/z: 530.8 (M+H)⁺.

Intermediate I-1442-ethoxy-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

Intermediate I-144A: 5-bromo-2-ethoxy-7-methylquinoxaline

Intermediate I-1G (372 mg, 1.287 mmol) was suspended in EtOH (10 mL) andwas mixed with 21% sodium ethoxide in ethanol (2 mL, 5.36 mmol). Mixturewas stirred at 40° C. for 1 hour. The solvent was removed on rotavaporand residue was dissolved in 20 mL of EtOAc and 15 mL of water. Thelayers were separated and the aqueous layer was extracted with EtOAc (10mL×2). The combined organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated. Crude product was loaded on ISCO (24g column, 0-50% EtOAC/Hexane gradient) to yield Intermediate I-144A (292mg, 1.093 mmol, 85% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.58 (s, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.65 (s, 1H), 4.50 (q, J=7.0 Hz,2H), 2.50 (s, 3H), 1.42 (t, J=7.0 Hz, 3H) LC-MS: method H, RT=1.14 min,MS (ESI) m/z: 269.1 (M+H)⁺.

Intermediate I-144

In a sealed tube, Intermediate I-144A (290 mg, 1.086 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (551 mg,2.171 mmol), potassium acetate (213 mg, 2.171 mmol) were mixed in1,4-dioxane (5 mL). After degassing with bubbling N₂ for 10 minutes,Pd(dppf)Cl₂CH₂Cl₂ adduct (44.3 mg, 0.054 mmol) was added. The vial wassealed and was heated at 120° C. for 60 minutes. The reaction mixturewas cooled room temperature and loaded on celite. Purified on ISCO (40 gcolumn, 0-50% EtOAc/Hexane in 18 minutes) to yield I-144 (0.311 g, 0.990mmol, 91% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (s, 1H), 7.91 (s,1H), 7.68 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.26 (br. s., 3H), 1.41 (t,J=7.0 Hz, 3H), 1.34 (s, 12H). LC-MS: method H, RT=0.94 min, MS (ESI)m/z: 233.0 (M+H)⁺. See mass of boronic acid.

Example 1 5-(benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline

A mixture of Intermediate I-1G (40 mg, 0.138 mmol),benzofuran-2-ylboronic acid (28.0 mg, 0.173 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (6.78 mg, 8.30 μmol) in toluene (1.8 mL) andEtOH (0.600 mL) was degassed with argon for 2.0 min. To this solutionwas added sodium carbonate (2M, 0.121 mL, 0.242 mmol). The mixture washeated in a microwave reactor at 100° C. for 30 min. The reactionmixture was diluted with EtOAc/water. The organic layer was collected,dried over sodium sulfate. The crude residue was dissolved inDMSO/acetonitrile (6 mL/6 mL), purified using a preparative HPLC (methodA, 70-100% B in 10 min, flow rate of 40 mL/min). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto give Example 1 (28 mg, 0.085 mmol, 61.4% yield) as yellow lyophilate.¹H NMR (500 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 8.13(d, J=0.8 Hz, 1H), 7.85 (t, J_(HF)=71.85 Hz, 1H), 7.79 (dd, J=7.7, 0.6Hz, 1H), 7.75 (dd, J=1.8, 1.0 Hz, 1H), 7.68 (dd, J=8.3, 0.8 Hz, 1H),7.41 (ddd, J=8.3, 7.2, 1.1 Hz, 1H), 7.34-7.30 (m, 1H), 2.66 (s, 3H); ¹⁹FNMR (471 MHz, DMSO-d₆) δ −88.42 (s, 2F); LC-MS: Method A, 50 to 100% B.RT=2.32 min, MS (ESI) m/z: 327.1 (M+H)⁺. Analytical HPLC (low pH, 254nM): Sunfire, RT=12.62 min, 100% purity; XBridge, RT=8.29 min, 99%purity.

Example 22-(difluoromethoxy)-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline

Intermediate 2A: (5-methoxybenzofuran-2-yl)boronic acid

To 5-methoxybenzofuran (188 mg, 1.269 mmol) in THF (4.0 mL) at −78° C.was added 1.6 N n-BuLi in hexanes (1.190 mL, 1.903 mmol) dropwise. Thesolution became slightly yellow. The reaction mixture was stirred at−78° C. for 20 min, followed by addition of triisopropyl borate (0.737mL, 3.17 mmol). After 30 min stirring at −78° C., the cooling bath wasremoved and the stirring was continued at room temperature for 1.5 h.The reaction mixture was diluted with EtOAc, quenched with 3.0 mL of 1.0N HCl. After stirring at room temperature for 25 min, the organic layerwas collected, washed with brine and dried over sodium sulfate. Afterevaporation of solvent, the crude product was dissolved in a smallamount of chloroform/a drop of MeOH and charged to a 4 g silica gelcartridge which was eluted with hexanes for 2 min., then a 10 mingradient from 0% to 60%. The desired fractions were combined,concentrated and lyophilized to give Intermediate 2A (170 mg, 0.886mmol, 69.8% yield) as a white solid. ¹H NMR (500 MHz, methanol-d₄) δ7.41 (d, J=9.1 Hz, 1H), 7.30 (s, 1H), 7.14 (d, J=2.5 Hz, 1H), 6.96 (dd,J=8.9, 2.6 Hz, 1H), 3.84 (s, 3H); LC-MS: method A, RT=1.45 min, MS (ESI)m/z: 149.0 (M-B(OH)₂)⁺.

Example 2

A mixture of Intermediate I-1G (22 mg, 0.076 mmol), Intermediate 2A(18.26 mg, 0.095 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (4.97 mg, 6.09 μmol) in toluene (1.5 mL) andEtOH (0.5 mL) was degassed with argon for 2.0 min. To this solution wasadded sodium carbonate (2M, 0.067 mL, 0.133 mmol). The reaction mixturewas heated in a microwave reactor at 100° C. for 30 min, then dilutedwith EtOAc/water. The organic layer was collected, dried over sodiumsulfate. After evaporation of solvent, the crude residue was dissolvedin DMSO/MeOH (6 mL/4 mL), purified using a preparative HPLC (method A,70-100% B in 10 min, flow rate of 40 mL/min). The desired fractions wereplaced in a SpeedVac overnight to remove solvent, then lyophilized togive Example 2 (15 mg, 0.042 mmol, 54.8% yield) as yellow lyophilate. ¹HNMR (500 MHz, DMSO-d₆) δ 8.90 (s, 1H), 8.21 (d, J=1.4 Hz, 1H), 8.05 (s,1H), 7.88 (t, J_(HF)=71.53 Hz, 1H), 7.75 (s, 1H), 7.58 (d, J=8.8 Hz,1H), 7.30 (d, J=2.8 Hz, 1H), 6.98 (dd, J=8.9, 2.6 Hz, 1H), 3.82 (s, 3H),2.63 (s, 3H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ −87.80 (s, 2F); LC-MS: MethodA, 50 to 100% B. RT=2.27 min, MS (ESI) m/z: 357.0 (M+H)⁺. AnalyticalHPLC (low pH, 254 nM): Sunfire, RT=12.92 min, 99% purity; XBridge,RT=9.70 min, 99% purity.

Example 3 2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]oxazole

Intermediate 3A: 2-iodobenzo[d]oxazole

To magnesium bromide (52 mg, 0.282 mmol) in THF (0.5 mL) cooled at −10°C. was added 1.6 N n-BuLi in hexanes (0.530 mL, 0.847 mmol) dropwise.The reaction mixture was stirred between −10° C. and 0° C. for 1.0 h.Benzo[d]oxazole (101 mg, 0.847 mmol) in THF (0.5 mL) was added, and thebrown mixture was stirred at room temperature for 2.0 h. Iodine (79 mg,0.311 mmol) in THF (0.5 mL) was added, and the reaction mixture wasstirred at room temperature for 18 h. The mixture was diluted withEtOAc, quenched with 10% Na₂S₂O₃. The organic layer was washed withwater, brine and dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 12 g silica gel cartridge which was eluted with hexanesfor 3 min., then a 15 min gradient from 0% to 30%. The desired fractionswere combined and concentrated to give Intermediate 3A (47 mg, 0.192mmol, 67.9% yield) as a solid. ¹H NMR (400 MHz, chloroform-d) δ7.67-7.60 (m, 1H), 7.50-7.44 (m, 1H), 7.28-7.20 (m, 2H); LC-MS: methodA, RT=1.73 min, MS (ESI) m/z: 246.0 (M+H)⁺.

Example 3

To Intermediate I-1 (31 mg, 0.092 mmol), Intermediate 3A (29.4 mg, 0.120mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex with dichloromethane (1:1) (6.03 mg, 7.38 μmol) was addedtoluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.101mL, 0.203 mmol). The reaction mixture was heated in a microwave reactorat 110° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. To the reaction mixture was added EtOAc/water. The organiclayer was collected, dried over sodium sulfate. After evaporation ofsolvent, the crude residue was purified using a preparative HPLC (methodA, 40-100% B in 10 min, flow rate of 40 mL/min). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto give Example 3 (27 mg, 0.082 mmol, 89% yield) as a white lyophilate.¹H NMR (500 MHz, acetonitrile-d₃) 8.74 (br. s., 1H), 8.32 (d, J=1.9 Hz,1H), 7.93 (br. s., 1H), 7.89-7.85 (m, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.71(t, J_(HF)=71.53 Hz, 1H), 7.53-7.45 (m, 2H), 2.69 (s, 3H); ¹⁹F NMR (471MHz, acetonitrile-d₃) δ −90.12 (s, 2F); LC-MS: Method A, 40 to 100% B.RT=1.81 min, MS (ESI) m/z: 328.0 (M+H)⁺. Analytical HPLC (low pH, 254nM): Sunfire, RT=9.41 min, 99% purity; XBridge, RT=7.19 min, 99% purity.

Example 42-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole

To a microwave reaction tube was chargeddichlorobis(chloro-di-tert-butylphosphine)palladium (1.118 mg, 2.076μmol), Cu(Xantphos)I (6.39 mg, 8.30 μmol), cesium carbonate (85 mg,0.259 mmol), benzo[d]thiazole (0.017 mL, 0.156 mmol) and IntermediateI-1G (30 mg, 0.104 mmol). Toluene (1.0 mL) was added and the reactionmixture was sealed and heated at 100° C. The mixture was diluted withEtOAc/water, the organic layer was collected, dried over sodium sulfate.The crude residue was purified using a preparative HPLC (method A,60-100% B in 10 min, flow rate of 40 mL/min). The desired fractions wereplaced in a SpeedVac overnight to remove solvent, then lyophilized togive Example 4 (2.2 mg, 6.34 μmol, 6.11% yield) as a white lyophilate.¹H NMR (500 MHz, acetonitrile-d₃) δ 8.84 (d, J=1.7 Hz, 1H), 8.78 (s,1H), 8.15-8.11 (m, 2H), 7.87 (dd, J=1.8, 1.0 Hz, 1H), 7.72 (t,J_(HF)=71.82 Hz, 1H), 7.59 (ddd, J=8.2, 7.1, 1.2 Hz, 1H), 7.50 (td,J=7.6, 1.1 Hz, 1H), 2.72 (s, 3H); ¹⁹F NMR (471 MHz, acetonitrile-d₃) δ−90.06 (s, 2F); LC-MS: Method H, 50 to 100% B. RT=1.93 min, MS (ESI)m/z: 344.2 (M+H)⁺. Analytical HPLC (low pH, 254 nM): Sunfire, RT=12.49min, 100% purity; XBridge, RT=9.38 min, 99% purity.

Example 5 2-(difluoromethoxy)-5-(1H-indol-2-yl)-7-methylquinoxaline

Intermediate 5A: tert-butyl 2-(tributylstannyl)-1H-indole-1-carboxylate

To diisopropylamine (0.984 mL, 6.90 mmol) in THF (12 mL) at −78° C. wasadded 1.6 N n-BuLi in hexanes (4.32 mL, 6.90 mmol). The reaction mixturewas stirred at −78° C. for 0.5 h. Next, tert-butyl1H-indole-1-carboxylate (0.935 mL, 4.60 mmol) was added, and thereaction mixture was stirred at −78° C. for 0.5 h. Tributyltin chloride(1.489 mL, 5.52 mmol) was added, and the reaction mixture was stirred at−78° C. for 0.5 h, then at room temperature for 1.5 h. The reactionmixture was diluted with EtOAc, quenched with saturated ammoniumchloride. The organic layer was washed with brine, dried over sodiumsulfate. After evaporation of solvent, the crude product was dissolvedin a small amount of chloroform and charged to a 40 g silica gelcartridge which was eluted with hexanes for 3 min., then a 18 mingradient from 0% to 30%. The desired fractions were combined andconcentrated to give Intermediate 5A (2.1 g, 4.15 mmol, 90% yield) asclear oil. ¹H NMR (500 MHz, chloroform-d) δ 7.98-7.94 (m, 1H), 7.54-7.50(m, 1H), 7.26-7.15 (m, 2H), 6.74-6.69 (m, 1H), 1.71 (s, 9H), 1.58-1.49(m, 7H), 1.33 (sxt, J=7.3 Hz, 6H), 1.11-1.06 (m, 5H), 0.89 (t, J=7.4 Hz,9H); LC-MS: Method A, 60 to 100% B. RT=1.86 min, MS (ESI) m/z: notobserved.

Example 5

A solution of Intermediate 5A (65.7 mg, 0.130 mmol) and IntermediateI-1G (30 mg, 0.104 mmol) in toluene (1.2 mL) was degassed with argon for3 min. Tetrakis(triphenylphosphine)palladium(O) (6.00 mg, 5.19 μmol) wasadded. The reaction mixture was sealed and heated in a microwave reactorat 125° C. for 30 min. HPLC and LCMS indicated only 15% conversion. Thenanother portion of Intermediate 5A (65.7 mg, 0.130 mmol) andtetrakis(triphenylphosphine)palladium(O) (6.00 mg, 5.19 μmol) wereadded, and the reaction mixture was heated at 125° C. for another 1.0 h.Toluene was removed under vacuum. 4.0 N HCl in dioxane (2.076 mL, 8.30mmol) was added and the reaction mixture was stirred at room temperatureovernight. Solvent was removed in vacuum. The crude residue was purifiedusing a preparative HPLC (method A, 50-100% B in 10 min, flow rate of 40mL/min). The desired fractions were placed in a SpeedVac overnight toremove solvent, then lyophilized to give Example 5 (5.0 mg, 0.014 mmol,13.92% yield) as yellow lyophilate. ¹H NMR (500 MHz, acetonitrile-d₃) δ8.72 (s, 1H), 8.26 (d, J=1.7 Hz, 1H), 7.71 (t, J_(HF)=71.82 Hz, 1H),7.68 (d, J=8.0 Hz, 1H), 7.65 (d, J=0.8 Hz, 1H), 7.61 (dd, J=8.3, 0.8 Hz,1H), 7.30-7.28 (m, 1H), 7.23 (ddd, J=8.1, 7.0, 1.1 Hz, 1H), 7.12 (td,J=7.5, 1.0 Hz, 1H), 2.65 (s, 3H); ¹⁹F NMR (471 MHz, acetonitrile-d₃) δ−90.04 (s, 2F); LC-MS: Method H, 0 to 100% B. RT=1.88 min, MS (ESI) m/z:326.3 (M+H)⁺. Analytical HPLC (method A): Sunfire, RT=11.54 min, 99%purity; XBridge, RT=9.21 min, 90% purity.

Example 62-(difluoromethoxy)-5-(4,5-dimethoxybenzofuran-2-yl)-7-methylquinoxaline

Intermediate 6A: 5-(hydroxymethylene)-6,7-dihydrobenzofuran-4(5H)-one

To sodium hydride (1.175 g, 29.4 mmol) and potassium hydride (0.098 g,0.734 mmol) in THF (25 mL) at 0° C. was added ethyl formate (2.99 mL,36.7 mmol), followed by addition of 6,7-dihydrobenzofuran-4(5H)-one (1.0g, 7.34 mmol) in THF (5.0 mL) dropwise. The reaction mixture was stirredat room temperature for 1.0 h and heated at 50° C. for 1.5 h. HPLC andLCMS indicated a completion of reaction. The mixture was diluted withEtOAc, cooled to 0° C., quenched with 3.0 mL MeOH/water, pH was adjustedto 7 with 1.0 N HCl. The organic layer was collected, washed with brine,dried over sodium sulfate. After evaporation of solvent, Intermediate 6A(1.36 g, 8.28 mmol, 113% yield) was obtained as yellow liquid. It wasused for the next step without further purification. ¹H NMR indicated amixture of the keto and enol form in a ratio of 1:7. ¹H NMR of the enolform: (500 MHz, chloroform-d) δ 7.39-7.36 (m, 1H), 7.31-7.26 (m, 1H),6.74 (d, J=2.2 Hz, 1H), 2.93-2.87 (m, 2H), 2.68 (td, J=7.0, 0.8 Hz, 2H);LC-MS: method A, RT=1.19 and 1.35 min, MS (ESI) m/z: 165.0 (M+H)⁺.

Intermediate 6B: 4-hydroxybenzofuran-5-carbaldehyde

To a suspension of DDQ (2.074 g, 9.14 mmol) in dioxane (6.0 mL) wasadded Intermediate 6A (1.2 g, 7.31 mmol) in dioxane (7.0 mL) dropwise.The reaction mixture was stirred at room temperature for 2.0 h. TLCindicated a completion of the reaction. It was diluted with EtOAc,stirred for 15 min. The precipitate was filtered and the filtrate wasconcentrated. The crude was triturated with chloroform and theprecipitate was removed by filtration. The filtrate was concentrated,dissolved in a small amount of chloroform and charged to a 80 g silicagel cartridge which was eluted with hexanes for 3 min., then a 15 mingradient from 0% to 40%. The desired fractions were combined andconcentrated to give Intermediate 6B (0.66 g, 4.07 mmol, 55.7% yield) asa slightly brown solid. ¹H NMR (500 MHz, chloroform-d) δ 12.01 (s, 1H),9.94 (s, 1H), 7.63 (d, J=2.2 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.18 (dd,J=8.7, 1.0 Hz, 1H), 7.03 (dd, J=2.2, 0.8 Hz, 1H); LC-MS: method A,RT=1.65 min, MS (ESI) m/z: 163.0 (M+H)⁺.

Intermediate 6C: 4-methoxybenzofuran-5-carbaldehyde

To Intermediate 6B (0.66 g, 4.07 mmol) in DMF (6.0 mL) was addedpotassium carbonate (1.547 g, 11.19 mmol), followed by iodomethane(0.445 mL, 7.12 mmol). The mixture was allowed to stir at roomtemperature overnight. The reaction mixture was diluted withEtOAc/water. The organic layer was collected, washed with brine, driedover sodium sulfate. After evaporation of solvent, Intermediate 6C (0.68g, 3.86 mmol, 95% yield) was obtained as a white solid. It was used forthe next step without further purification. ¹H NMR (500 MHz,chloroform-d) δ 10.51 (d, J=0.8 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.66(d, J=2.2 Hz, 1H), 7.28-7.24 (m, 1H), 7.08 (dd, J=2.2, 0.8 Hz, 1H), 4.29(s, 3H); LC-MS: method A, RT=1.62 min, MS (ESI) m/z: 177.0 (M+H)⁺.

Intermediate 6D: 4-methoxybenzofuran-5-yl formate

To a stirred solution of Intermediate 6C (0.31 g, 1.760 mmol) indichloromethane (4.0 mL) was added mCPBA (0.557 g, 2.420 mmol).Trifluoroacetic acid (0.136 mL, 1.760 mmol) in dichloromethane (2.0 mL)was added. The reaction mixture was stirred at room temperature for 2.0h. Sodium thiosulfite (10%, 1.0 mL) was added to quench the reaction.Solvent was removed under vacuum. The residue was partitioned betweenEtOAc/saturated sodium bicarbonate. The organic layer was collected,washed with saturated sodium bicarbonate, brine and dried over sodiumsulfate. After evaporation of solvent, Intermediate 6D (0.34 g, 1.769mmol, 101% yield) was obtained as brown oil that was used for next stepwithout further purification. LC-MS: method A, RT=1.53 min, MS (ESI)m/z: 215.0 (M+Na)⁺.

Intermediate 6E: 4-methoxybenzofuran-5-ol

To Intermediate 6D (0.34 g, 1.769 mmol) in MeOH (5.0 mL) was addedpotassium carbonate (0.428 g, 3.10 mmol). The mixture was allowed tostir at room temperature for 20 min. MeOH was removed under vacuum. Theresidue was partitioned between EtOAc/water. The organic layer wascollected, washed with brine, dried over sodium sulfate. Afterevaporation of solvent, the crude product was dissolved in a smallamount of chloroform and charged to a 12 g silica gel cartridge whichwas eluted with hexanes for 2 min., then a 15 min gradient from 0% to40%. The desired fractions were combined and concentrated to giveIntermediate 6E (0.22 g, 1.340 mmol, 76% yield) as viscous oil. ¹H NMR(500 MHz, chloroform-d) δ 7.57 (d, J=2.2 Hz, 1H), 7.13 (dd, J=8.7, 1.0Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.88 (dd, J=2.2, 0.8 Hz, 1H), 4.13 (s,3H); LC-MS: method A, RT=1.40 min, MS (ESI) m/z: 187.0 (M+Na)⁺.

Intermediate 6F: 4-methoxy-5-(methoxymethoxy)benzofuran

To Intermediate 6E (0.21 g, 1.279 mmol) in DMF (4.0 mL) at 0° C. wasadded sodium hydride (0.070 g, 1.759 mmol, 60% in mineral). The reactionmixture was stirred at 0° C. for 5 min, and at room temperature for 10min. The mixture turned to deep blue color. Chloromethyl methyl ether(0.136 mL, 1.791 mmol) was added slowly, and the reaction mixture wasstirred at room temperature for 30 min. HPLC and TLC indicated acompletion of the reaction. The mixture was diluted with EtOAc, washedwith water, brine. The organic layer was dried over sodium sulfate.After evaporation of solvent, the crude product was dissolved in a smallamount of chloroform and charged to a 12 g silica gel cartridge whichwas eluted with hexanes for 3 min., then a 12 min gradient from 0% to30%. The desired fractions were combined and concentrated to giveIntermediate 6F (0.24 g, 1.153 mmol, 90% yield). ¹H NMR (500 MHz,chloroform-d) δ 7.56 (d, J=2.2 Hz, 1H), 7.18-7.13 (m, 2H), 6.91 (dd,J=2.2, 0.6 Hz, 1H), 5.21 (s, 2H), 4.10 (s, 3H), 3.59 (s, 3H); LC-MS:method A, RT=1.70 min, MS (ESI) m/z: 231.0 (M+H)⁺.

Intermediate 6G: (4-methoxy-5-(methoxymethoxy)benzofuran-2-yl)boronicacid

To Intermediate 6F (0.236 g, 1.133 mmol) in THF (4.0 mL) at −78° C. wasadded 1.6 N n-BuLi in hexanes (1.240 mL, 1.984 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 30 min, followed by additionof triisopropyl borate (0.790 mL, 3.40 mmol). The reaction mixture wasstirred for 30 min, and the cooling bath was removed to allow warm up toroom temperature for 1.0 h. TLC and HPLC indicated a completion of thereaction. The reaction mixture was diluted with EtOAc and quenched with4.0 mL of 0.5 N HCl. After stirring at room temperature for 10 min, theorganic layer was collected, washed with brine and dried over sodiumsulfate. After evaporation of solvent, the crude product was dissolvedin a small amount of chloroform and charged to a 4 g silica gelcartridge which was eluted with 5% for 2 min., then a 5 min gradientfrom 5% to 85%. The desired fractions were combined, concentrated andlyophilized to give Intermediate 6G (0.23 g, 0.913 mmol, 81% yield) as awhite solid. ¹H NMR (400 MHz, methanol-d₄) δ 7.39 (s, 1H), 7.06 (s, 2H),5.06 (s, 2H), 4.72 (br. s., 1H), 3.98 (s, 3H), 3.46 (s, 3H); LC-MS:method A, RT=1.42 min, MS (ESI) m/z: 177.0.

Intermediate 6H2-(difluoromethoxy)-5-(4-methoxy-5-(methoxymethoxy)benzofuran-2-yl)-7-methylquinoxaline

A mixture of Intermediate I-1G (30 mg, 0.104 mmol), Intermediate 6G(32.7 mg, 0.130 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (5.93 mg, 7.26 μmol) in toluene (1.8 mL) andEtOH (0.600 mL) was degassed with argon for 2.0 min. To this solutionwas added sodium carbonate (2M, 0.104 mL, 0.208 mmol). The mixture washeated in a microwave reactor at 100° C. for 30 min, at which time HPLCand LCMS indicated a completion of the reaction. The reaction mixturewas diluted with EtOAc/water. The organic layer was collected, driedover sodium sulfate. The crude residue was dissolved inDMSO/acetonitrile (2 mL/3 mL), purified using a preparative HPLC (methodA, 50-100% B in 10 min; RT=9.5 min). The desired fractions were placedin a SpeedVac overnight to remove solvent, then lyophilized to giveIntermediate 6H (26 mg, 0.060 mmol, 57.8% yield) as yellow lyophilate.¹H NMR (500 MHz, acetonitrile-d₃) δ 8.75 (s, 1H), 8.27 (d, J=1.9 Hz,1H), 8.25 (d, J=0.8 Hz, 1H), 7.72 (dd, J=1.9, 1.1 Hz, 1H), 7.71 (t,J_(HF)=71.80 Hz, 1H), 7.29-7.25 (m, 1H), 7.22-7.19 (m, 1H), 5.20 (s,2H), 4.14 (s, 3H), 3.55 (s, 3H), 2.67 (s, 3H); ¹⁹F NMR (471 MHz,acetonitrile-d₃) δ −90.01 (s, 2F); LC-MS: Method A, 50 to 100% B.RT=2.19 min, MS (ESI) m/z: 417.1 (M+H)⁺. Analytical HPLC (method A):Sunfire, RT=12.38 min, 99% purity; XBridge, RT=9.66 min, 94% purity.

Intermediate 6I2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methoxybenzofuran-5-ol

To Intermediate 6H (16 mg, 0.038 mmol) in THF (1.5 mL) and MeOH (0.5 mL)was added 6.0 N HCl (0.640 mL, 3.84 mmol). The reaction mixture wasstirred at 60° C. for 1.0 h. HPLC indicated a completion of thereaction. It was diluted with EtOAc, washed with water, brine. Theorganic layer was collected, dried over sodium sulfate. Afterevaporation of solvent, Intermediate 6I (13 mg, 0.035 mmol, 91% yield)was obtained as a brown solid that was used for next step withoutfurther purification. ¹H NMR (500 MHz, acetonitrile-d₃) δ 8.72 (s, 1H),8.21 (d, J=5.0 Hz, 2H), 7.69 (t, J_(HF)=71.53 Hz, 1H), 7.68 (br. s.,1H), 7.18 (d, J=8.5 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.53 (br. s., 1H),4.14 (s, 3H), 2.65 (s, 3H); ¹⁹F NMR (471 MHz, acetonitrile-d₃) δ −89.92(br. s., 2F); LC-MS: method A, RT=1.86 min, MS (ESI) m/z: 373.0 (M+H)⁺.

Example 6

To a stirred solution of Intermediate 6I (13 mg, 0.035 mmol) and cesiumcarbonate (28.4 mg, 0.087 mmol) in DMF (0.8 mL) at room temperature wasadded methyl iodide (3.82 μl, 0.061 mmol) in acetonitrile (0.03 mL). Thereaction mixture was stirred at room temperature for 1.0 h. HPLC andLCMS indicated a completion of the reaction. The mixture was dilutedwith EtOAc, quenched with 0.2 N HCl (2.0 mL). The organic layer wascollected, dried over sodium sulfate. After evaporation of solvent, thecrude was purified using a preparative HPLC (method A, 60-100% B in 10min; RT=8.5 min). The desired fractions were placed in a SpeedVacovernight to remove solvent, then lyophilized to give Example 6 (9.5 mg,0.024 mmol, 68.3% yield) as yellow lyophilate. ¹H NMR (500 MHz,acetonitrile-d₃) δ 8.74 (s, 1H), 8.24 (d, J=1.7 Hz, 1H), 8.19 (s, 1H),7.71 (t, J_(HF)=71.80 Hz, 1H), 7.70 (s, 1H), 7.27 (d, J=8.8 Hz, 1H),7.12 (d, J=8.8 Hz, 1H), 4.09 (s, 3H), 3.91 (s, 3H), 2.66 (s, 3H); ¹⁹FNMR (471 MHz, acetonitrile-d₃) δ −90.01 (s, 2F); LC-MS: Method A, 50 to100% B. RT=2.15 min, MS (ESI) m/z: 387.0 (M+H)⁺. Analytical HPLC (methodA): Sunfire, RT=12.88 min, 100% purity; XBridge, RT=10.21 min, 96%purity.

Example 76-(benzyloxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole

To a stirred solution of Intermediate I-4D (10 mg, 0.028 mmol) andcesium carbonate (22.67 mg, 0.070 mmol) in DMF (0.6 mL) at roomtemperature was added benzyl bromide (5.79 μl, 0.049 mmol) inacetonitrile (0.03 mL). The reaction mixture was stirred at roomtemperature for 3 h. HPLC and LCMS indicated a completion of thereaction. The mixture was diluted with EtOAc, quenched with 0.2 N HCl(2.0 mL). The organic layer was collected, dried over sodium sulfate.After evaporation of solvent, the crude was purified via preparativeLC/MS (method D), 55-95% B over 10 minutes. Fractions containing thedesired product were combined and dried via centrifugal evaporation toyield Example 7 (12.1 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 1H),8.73 (d, J=1.4 Hz, 1H), 8.05-8.02 (m, 1H), 7.90 (d, J=5.8 Hz, 1H), 7.89(t, J_(HF)=71.53 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.53 (d, J=7.4 Hz,2H), 7.43 (t, J=7.4 Hz, 2H), 7.39-7.35 (m, 1H), 7.26 (dd, J=8.8, 2.5 Hz,1H), 5.23 (s, 2H), 2.67 (s, 3H); LC-MS: Method A, 0 to 100% B. RT=3.33min, MS (ESI) m/z: 450.0 (M+H)⁺. Analytical HPLC purity (method B):100%.

Example 84-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 8A: 4-chloro-2-iodobenzo[d]thiazole

To a suspension of 4-chlorobenzo[d]thiazol-2-amine (0.66 g, 3.57 mmol)and p-TSA monohydrate (2.040 g, 10.72 mmol) in acetonitrile (16 mL) at10° C. (cooled with ice water) was added dropwise a solution of sodiumnitrite (0.493 g, 7.15 mmol) and potassium iodide (1.483 g, 8.94 mmol)in water (4 mL) over a period of 25 min. The reaction mixture wasstirred at 10° C. for 10 min, and allowed to warm up to room temperatureand stirred over the weekend. To the reaction mixture was added sodiumbicarbonate (pH to 9.0), water and EtOAc. The organic layer wascollected, washed with water, saturated Na₂S₂O₃, water, brine and driedover sodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform/toluene/MeOH and charged to a40 silica gel cartridge which was eluted with hexanes for 3 min., then a18 min gradient from 0% to 30%. The desired fractions were combined andconcentrated to give Intermediate 8A (0.571 g, 1.932 mmol, 54.1% yield)as a white solid. ¹H NMR (500 MHz, chloroform-d) δ 7.77 (dd, J=8.1, 1.0Hz, 1H), 7.49 (dd, J=7.8, 1.0 Hz, 1H), 7.38-7.33 (m, 1H); LC-MS: methodA, RT=1.94 min, MS (ESI) m/z: 296.0 and 298.0 (M+H)⁺.

Example 8

To Intermediate I-1 (16 mg, 0.048 mmol), Intermediate 8A (20 mg, 0.067mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex with dichloromethane (1:1) (3.0 mg, 3.67 μmol) was added toluene(1.2 mL) and EtOH (0.4 mL). The mixture was sonicated for 1 min, andflushed with argon. To this was added sodium carbonate (2M, 0.052 mL,0.105 mmol). The reaction mixture was heated in a microwave reactor at110° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. To the reaction mixture was added EtOAc/water. The organiclayer was collected, dried over sodium sulfate. After evaporation ofsolvent, the crude material was purified via preparative LC/MS (methodD, 55-90% B over 10 minutes). Fractions containing the desired productwere combined and dried via centrifugal evaporation to yield the Example8 (4.2 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.79 (d, J=1.4 Hz,1H), 8.19 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.90 (t, J_(HF)=71.53 Hz,1H), 7.68 (d, J=7.7 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 2.71 (s, 3H);LC-MS: Method H, 0 to 100% B. RT=3.66 min, MS (ESI) m/z: 378.0 (M+H)⁺.Analytical HPLC purity (method B): 100%.

Example 92-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)thiazolo[4,5-b]pyridine

Intermediate 9A: 2-chlorothiazolo[4,5-b]pyridine

To a slurry of thiazolo[4,5-b]pyridine-2-thiol (343 mg, 2.039 mmol) indichloromethane (0.5 mL) was added sulfuryl chloride (3.32 mL, 40.8mmol). The suspension was stirred at 50° C. for 2.0 h, and at roomtemperature overnight. To the yellow suspension was added ice water,stirred at room temperature for 15 min to decompose the excess sulfurylchloride. EtOAc and 4.0 N NaOH were added to adjust the pH to 10-12. Theorganic layer was collected, washed with brine, dried over sodiumsulfate. After evaporation of solvent, the crude product was dissolvedin a small amount of chloroform and charged to a 12 g silica gelcartridge which was eluted with 5% for 3 min., then a 12 min gradientfrom 5% to 60%. The desired fractions were combined and concentrated togive Intermediate 9A (265 mg, 1.553 mmol, 76% yield) as a white solid.¹H NMR (500 MHz, chloroform-d) δ 8.76 (dd, J=5.0, 1.7 Hz, 1H), 8.19 (dd,J=8.0, 1.7 Hz, 1H), 7.39 (dd, J=8.0, 4.7 Hz, 1H); LC-MS: method A,RT=1.22 min, MS (ESI) m/z: 171 and 173 (M+H)⁺.

Example 9

To Intermediate I-1 (17 mg, 0.051 mmol), Intermediate 9A (11.22 mg,0.066 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (3.30 mg, 4.05 μmol) was addedtoluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.056mL, 0.111 mmol). The reaction mixture was heated in a microwave reactorat 130° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. To the reaction mixture was added EtOAc/water. The mixture wasstirred at room temperature for 15 min. The organic layer was collected.After evaporation of solvent, the crude material was purified viapreparative LC/MS (method D, 40-90% B over 10 minutes) to yield theExample 9 (11.2 mg). ¹H NMR (500 MHz, methanol-d₄) δ 8.93 (d, J=1.7 Hz,1H), 8.73 (s, 1H), 8.72 (dd, J=4.7, 1.4 Hz, 1H), 8.47 (dd, J=8.0, 1.4Hz, 1H), 7.89 (s, 1H), 7.71 (t, J_(HF)=71.53 Hz, 1H), 7.61 (s, 1H), 7.44(dd, J=8.0, 4.7 Hz, 1H), 2.71 (s, 3H); LC-MS: Method H, 0 to 100% B.RT=2.59 min, MS (ESI) m/z: 345.0 (M+H)⁺. Analytical HPLC purity (methodB): 95%.

Example 102-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole

To Intermediate I-1 (25 mg, 0.074 mmol), Intermediate I-3 (24 mg, 0.093mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex with dichloromethane (1:1) (4.86 mg, 5.95 μmol) was addedtoluene (1.2 mL) and EtOH (0.4 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.082mL, 0.164 mmol). The reaction mixture was heated in a microwave reactorat 110° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. EtOAc/brine was added to the mixture. The organic layer wascollected, dried over sodium sulfate. After evaporation of solvent, thecrude was dissolved in DMF (3.5 mL) and was purified via preparativeLC/MS (method D, 60-100% B over 10 minutes) to yield Example 10 (15 mg).¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.73 (s, 1H), 7.89 (s, 1H),7.87 (t, J_(HF)=71.89 Hz, 1H), 7.55 (d, J=1.9 Hz, 1H), 7.02 (s, 1H),3.86 (s, 3H), 2.75 (s, 3H), 2.68 (s, 3H); LC-MS: method A, RT=2.66 min,MS (ESI) m/z: 388.0 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 11 tert-butyl2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

Intermediate 11A: tert-butyl2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

tert-Butyl nitrite (0.181 mL, 1.371 mmol) was added to copper (II)bromide (297 mg, 1.332 mmol) in dry acetonitrile (3.0 mL) under argon.The reaction mixture was stirred at room temperature for 10 min. Asuspension of tert-butyl2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (200 mg,0.783 mmol) in dry acetonitrile (4.0 mL) was added dropwise. Thereaction mixture was stirred at room temperature for 1.0 h. Acetonitrilewas removed under vacuum, the reaction mixture was diluted with EtOAc,quenched with 1.0 N HCl. The organic layer was collected, washed with0.5 N HCl (2×), saturated sodium bicarbonate, brine and dried oversodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 12 g silicagel cartridge which was eluted with hexanes for 2 min., then a 12 mingradient from 0% to 50%. The desired fractions were combined,concentrated and lyophilized to give Intermediate 11A (85 mg, 0.266mmol, 34.0% yield) as a white solid. ¹H NMR (500 MHz, acetonitrile-d₃) δ4.56 (t, J=1.8 Hz, 2H), 3.70 (t, J=5.8 Hz, 2H), 2.81-2.76 (m, 2H), 1.47(s, 9H); LC-MS: method A, RT=1.86 min, MS (ESI) m/z: 319.0 and 321.0(M+H)⁺.

Example 11

To Intermediate I-1 (30 mg, 0.089 mmol), Intermediate 11A (34.2 mg,0.107 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.83 mg, 7.14 μmol) was addedtoluene (2.1 mL) and EtOH (0.7 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.098mL, 0.196 mmol). The reaction mixture was heated in a microwave reactorat 120° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. To the reaction mixture was added EtOAc/water. The organiclayer was collected, dried over sodium sulfate. After evaporation ofsolvent, the crude product was purified via a prep LC/MS (method D) togive Example 11 (23.4 mg, 0.052 mmol, 57.9% yield): ¹H NMR (500 MHz,methanol-d₄) δ 8.66 (s, 1H), 8.49 (d, J=1.7 Hz, 1H), 7.76 (d, J=0.8 Hz,1H), 7.69 (t, J_(HF)=71.80 Hz, 1H), 4.76 (s, 2H), 3.83 (t, J=5.8 Hz,2H), 2.99 (t, J=5.6 Hz, 2H), 2.65 (s, 3H), 1.51 (s, 9H); LC-MS: methodA, RT=2.51 min, MS (ESI) m/z: 449.0 (M+H)⁺. Analytical HPLC purity(method B): 99%.

Example 122-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxy-4-methylbenzo[d]thiazole

Intermediate 12A: N-((5-methoxy-2-methylphenyl)carbamothioyl)benzamide

To a solution of 5-methoxy-2-methylaniline (1.47 g, 10.72 mmol) inacetone was added dropwise benzoyl isothiocyanate (1.924 g, 11.79 mmol).The reaction mixture was stirred at room temperature for 30 min. HPLCand LCMS indicated a completion of the reaction. Acetone was removedunder vacuum. The crude was triturated with EtOAc/hexanes (1:4). Theprecipitate was collected by filtration, dried under vacuum to giveIntermediate 12A (3.1 g, 10.32 mmol, 96% yield) as a green solid. ¹H NMR(500 MHz, chloroform-d) δ 12.33 (br. s., 1H), 9.14 (br. s., 1H),7.96-7.92 (m, 2H), 7.71-7.67 (m, 1H), 7.61-7.56 (m, 3H), 7.21 (d, J=8.5Hz, 1H), 6.83 (dd, J=8.4, 2.6 Hz, 1H), 3.84 (s, 3H), 2.33 (s, 3H);LC-MS: method A, RT=2.11 min, MS (ESI) m/z: 301(M+H)⁺.

Intermediate 12B: 1-(5-methoxy-2-methylphenyl)thiourea

To a solution of Intermediate 12A (3.1 g, 10.32 mmol) in THF (20 mL) andMeOH (10 mL) heated at 70° C. was added 4.0 N NaOH (7.74 mL, 31.0 mmol).The reaction mixture was stirred at 70° C. for 2.0 h. HPLC and TLCindicated a completion of the reaction. The mixture was then leftstirring at room temperature overnight. THF and MeOH were removed undervacuum. The crude product was then suspended in water. The precipitatewas collected by filtration, washed with water and dried in the airunder vacuum and then dried under high vacuum to give Intermediate 12B(1.6 g, 8.15 mmol, 79% yield) as a solid. ¹H NMR (500 MHz, DMSO-d₆) δ9.19 (s, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.76 (dd,J=8.3, 2.8 Hz, 1H), 3.31 (s, 3H), 2.11 (s, 3H); LC-MS: method A, RT=1.16min, MS (ESI) m/z: 197.0 (M+H)⁺.

Intermediate 12C: 7-methoxy-4-methylbenzo[d]thiazol-2-amine

To a suspension of Intermediate 12B (1.43 g, 7.29 mmol) in AcOH (20 mL)at room temperature was added benzyltrimethylammonium tribromide (2.84g, 7.29 mmol) in acetonitrile (15 mL) dropwise (15 min). The reactionmixture was stirred at room temperature overnight. HPLC and LCMSindicated a completion of the reaction. Most of the solvent was removedunder vacuum. The mixture was diluted with EtOAc, and the pH wasadjusted to 8 with 1.0 N NaOH. The insoluble material was removed byfiltration. The organic layer of the filtrate was collected, washed withsaturated sodium bicarbonate, brine, dried over sodium sulfate. Afterevaporation of solvent, Intermediate 12C (1.42 g, 7.31 mmol, 100% yield)was obtained as a solid. ¹H NMR and HPLC indicated >90% purity. It wasused for the next step without further purification. ¹H NMR (500 MHz,chloroform-d) δ 7.09 (dd, J=8.1, 0.7 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H),3.93 (s, 3H), 2.51 (s, 3H); LC-MS: method A, RT=1.28 min, MS (ESI) m/z:195.0 (M+H)⁺.

Intermediate 12D: 2-bromo-7-methoxy-4-methylbenzo[d]thiazole

Tert-butyl nitrite (0.225 mL, 1.699 mmol) was added to a solution ofcopper (II) bromide (354 mg, 1.586 mmol) in acetonitrile (5.0 mL). Thereaction mixture was stirred at room temperature for 10 min, followed byaddition of Intermediate 12C (220 mg, 1.133 mmol) in acetonitrile (3.0mL). The reaction mixture was stirred at room temperature 1.0 h. HPLCand LCMS indicated a complete conversion of starting material to thedesired mono-bromo and undesired di-bromo product. Acetonitrile wasremoved under vacuum, the reaction mixture was diluted with EtOAc,quenched with 1.0 N HCl. The organic layer was collected, washed with0.5 N HCl (2×), saturated sodium bicarbonate, brine and dried oversodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 40 g silicagel cartridge which was eluted with hexanes for 2 min., then a 18 mingradient from 0% to 20%. TLC indicated the two products were notseparated by ISCO column. The crude residue was then purified using apreparative HPLC (method A, 50-100% B in 10 min., RT=7.0 min). Thedesired fractions were placed in a SpeedVac overnight to remove solvent,then lyophilized to give Intermediate 12D (120 mg, 0.465 mmol, 41.0%yield). ¹H NMR (500 MHz, chloroform-d) δ 7.22 (dd, J=8.0, 0.8 Hz, 1H),6.78 (d, J=8.0 Hz, 1H), 3.97 (s, 3H), 2.65 (d, J=0.8 Hz, 3H); LC-MS:method A, RT=2.17 min, MS (ESI) m/z: 258.0 and 260.0 (M+H)⁺.

Example 12

To Intermediate I-1 (20 mg, 0.059 mmol), Intermediate 12D (19.97 mg,0.077 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (3.89 mg, 4.76 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.074mL, 0.149 mmol). The reaction mixture was heated in a microwave reactorat 125° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. To the reaction mixture was added EtOAc/water. The organiclayer was collected, dried over sodium sulfate. After evaporation ofsolvent, the crude was dissolved in DMF (4.0 mL) and purified viapreparative LC/MS (method D, 60-100% B over 25 minutes). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to yield Example 12 (2.5 mg). ¹H NMR (500 MHz, DMSO-d₆) δ9.03 (s, 1H), 8.81 (d, J=1.9 Hz, 1H), 7.94 (s, 1H), 7.90 (t,J_(HF)=71.53 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H),3.99 (s, 3H), 2.73 (s, 3H), 2.70 (s, 3H); LC-MS: method A, RT=2.77 min,MS (ESI) m/z: 388.0 (M+H)⁺.

Example 132-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-difluoro-7-methoxybenzo[d]thiazol

Intermediate 13A: 4,6-difluoro-7-methoxybenzo[d]thiazol-2-amine

To 2,4-difluoro-5-methoxyaniline (270 mg, 1.697 mmol) in acetonitrile (6mL) was added ammonium thiocyanate (194 mg, 2.55 mmol). The reactionmixture was stirred at room temperature for 10 min. Thenbenzyltrimethylammonium tribromide (662 mg, 1.697 mmol) in acetonitrile(3.0 mL) was added dropwise (10 min). The mixture was then stirred atroom temperature overnight. HPLC and LCMS indicated a completion of thereaction. The mixture was diluted with EtOAc/saturated sodiumbicarbonate. The organic layer was collected, washed with brine, driedover sodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform/MeOH, and charged to a 12 gsilica gel cartridge which was eluted with 5% for 3 min., then a 12 mingradient from 5% to 75%. The desired fractions were combined andconcentrated to give Intermediate 13A (240 mg, 1.110 mmol, 65.4% yield)as a pale solid. ¹H NMR (500 MHz, methanol-d₄) δ 6.98 (dd, J=12.1, 10.5Hz, 1H), 3.99 (d, J=1.7 Hz, 3H); ¹⁹F NMR (471 MHz, methanol-d₄) δ−132.46 (s, 1F), −139.29 (s, 1F); LC-MS: method A, RT=1.54 min, MS (ESI)m/z: 217.0 (M+H)⁺.

Intermediate 13B: 2-chloro-4,6-difluoro-7-methoxybenzo[d]thiazole

To a solution of copper (II) chloride (82 mg, 0.611 mmol) inacetonitrile (6.0 mL) at 40° C. was added tert-butyl nitrite (0.087 mL,0.661 mmol), followed by Intermediate 13A (110 mg, 0.509 mmol) as asolid. The reaction mixture was stirred at 40° C. for 1.0 h, and leftstirring at room temperature overnight. It was diluted with EtOAc,washed with 0.5 HCl, saturated sodium bicarbonate and brine. Afterevaporation of solvent, Intermediate 13B (12 mg, 0.051 mmol, 10.01%yield) was obtained as yellow solid. ¹H NMR (500 MHz, chloroform-d) δ7.07 (dd, J=12.1, 9.6 Hz, 1H), 4.10 (d, J=2.2 Hz, 3H); ¹⁹F NMR (471 MHz,chloroform-d) δ −125.09 (s, 1F), −130.33 (s, 1F); LC-MS: method A,RT=2.01 min, MS (ESI) m/z: 236.0 and 238.0 (M+H)⁺.

Example 13

To Intermediate I-1 (12 mg, 0.036 mmol), Intermediate 13B (11.36 mg,0.048 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.332 mg, 2.86 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.045mL, 0.089 mmol). The reaction mixture was heated in a microwave reactorat 125° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. To the reaction mixture was added EtOAc/water. The organiclayer was collected, dried over sodium sulfate. After evaporation ofsolvent, the crude residue was purified using a preparative HPLC (methodA, 70-100% B in 10 min; RT=9.0 min). The desired fractions were placedin a SpeedVac overnight to remove solvent, then lyophilized to giveIntermediate 13 (2.0 mg, 4.84 μmol, 13.55% yield). ¹H NMR (500 MHz,acetonitrile-d₃) δ 8.84 (d, J=1.7 Hz, 1H), 8.82 (s, 1H), 7.91 (dd,J=1.9, 0.8 Hz, 1H), 7.73 (t, J_(HF)=71.80 Hz, 1H), 7.27 (dd, J=12.0,10.3 Hz, 1H), 4.15 (d, J=1.7 Hz, 3H), 2.73 (s, 3H); ¹⁹F NMR (471 MHz,acetonitrile-d₃) δ −89.97 (s, 2F), −127.74 (s, 1F), −133.31 (s, 1F);LC-MS: Method A, 50 to 100% B. RT=2.30 min, MS (ESI) m/z: 410.0 (M+H)⁺.Analytical HPLC (method A): Sunfire, RT=13.23 min, 99% purity; XBridge,RT=8.56 min, 99% purity.

Example 14 tert-butyl(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)carbamate

Intermediate 14A: methyl 2-bromobenzo[d]thiazole-7-carboxylate

Tert-butyl nitrite (1.111 mL, 8.40 mmol) was added to copper (II)bromide (1.770 g, 7.92 mmol) in dry acetonitrile (15 mL) under argon.The reaction mixture was stirred at room temperature for 10 min. Asuspension of methyl 2-aminobenzo[d]thiazole-7-carboxylate (1.0 g, 4.80mmol) in dry acetonitrile (15 mL) was added dropwise. The reactionmixture was stirred at room temperature for 1.5 h, then at 50° C. for 45min. HPLC and LCMS indicated a completion of the reaction. Acetonitrilewas removed under vacuum, the reaction mixture was diluted with EtOAc,quenched with 1.0 N HCl. The organic layer was collected, washed with0.5 N HCl (2×), saturated sodium bicarbonate, brine and dried oversodium sulfate. After evaporation of solvent, Intermediate 14A (1.2 g,4.41 mmol, 92% yield) was obtained as a brown solid. It was used fornext step without further purification. ¹H NMR (500 MHz, chloroform-d) δ8.19 (dd, J=8.0, 1.1 Hz, 1H), 8.13 (dd, J=7.7, 1.1 Hz, 1H), 7.58 (t,J=7.8 Hz, 1H), 4.05 (s, 3H); LC-MS: method A, RT=2.02 min, MS (ESI) m/z:272.0 274.0 (M+H)⁺.

Intermediate 14B: 2-bromobenzo[d]thiazole-7-carboxylic acid

To a solution of Intermediate 14A (0.64 g, 2.352 mmol) in THF (12 mL)was added lithium hydroxide monohydrate (0.296 g, 7.06 mmol) dissolvedin water (4.0 mL). The reaction mixture was stirred at room temperaturefor 2.5 h. HPLC indicated a completion of the reaction. The mixture wasdiluted with EtOAc, quenched with 0.5N HCl (20 mL). The organic layerwas collected, washed with brine, dried over sodium sulfate. Afterevaporation of solvent, Intermediate 14B (0.60 g, 2.325 mmol, 99% yield)was obtained as a yellow solid. It was used for next step withoutfurther purification. ¹H NMR (500 MHz, DMSO-d₆) δ 8.28 (dd, J=8.3, 1.1Hz, 1H), 8.12 (dd, J=7.7, 1.1 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H); LC-MS:method A, RT=1.76 min, MS (ESI) m/z: 258.0 and 260.0 (M+H)⁺.

Intermediate 14C: tert-butyl (2-bromobenzo[d]thiazol-7-yl)carbamate

To a suspension of Intermediate 14B (80 mg, 0.310 mmol) in THF (2.0 mL)was added TEA (0.065 mL, 0.465 mmol). The mixture turned to a clearsolution. To this solution was added trimethylsilyl azide (0.045 mL,0.341 mmol) and T₃P 50% wt in EtOAc (0.203 mL, 0.341 mmol). The reactionmixture was stirred at room temperature for 5 min, then tert-butanol(0.039 mL, 0.403 mmol) was added. The mixture was heated at 80° C. for2.0 h. Another 2.0 equivalents of triethylamine and 3 equivalents oft-BuOH were added, and the mixture was heated at 80° C. for 8.0 h. Thereaction mixture was diluted with EtOAc, washed with 0.5 N HCl, brine.The organic layer was dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 12 g silica gel cartridge which was eluted with hexanesfor 2 min., then a 15 min gradient from 0% to 30%. The desired fractionswere combined and concentrated to give Intermediate 14C (36 mg, 0.109mmol, 35.3% yield): a white solid. ¹H NMR (500 MHz, chloroform-d) δ 7.79(dd, J=7.8, 1.2 Hz, 1H), 7.51-7.43 (m, 2H), 6.48 (br. s., 1H), 1.58 (s,9H); LC-MS: method A, RT=1.99 min, MS (ESI) m/z: 329.0 and 331.0 (M+H)⁺.

Example 14

To Intermediate I-1 (28 mg, 0.083 mmol), Intermediate 14C (32.9 mg,0.100 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.44 mg, 6.66 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.104mL, 0.208 mmol). The reaction mixture was heated in a microwave reactorat 130° C. for 35 min. The mixture was diluted with EtOAc, washed withbrine. The organic layer was dried over sodium sulfate. Afterevaporation of solvent, the crude product was dissolved in a smallamount of chloroform and charged to a 4 g silica gel cartridge which waseluted with hexanes for 2 min., then a 10 min gradient from 0% to 30%.The desired fractions were combined and concentrated to give 20 mg ofthe crude product. This crude product was further purified by prep HPLC.The crude residue was purified using a preparative HPLC (method A,60-100% B in 10 min; RT=8.5 min). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to give Example14 (11 mg, 28% yield). ¹H NMR (500 MHz, chloroform-d) δ 8.78 (d, J=1.7Hz, 1H), 8.72 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.88 (dd, J=1.8, 1.0 Hz,1H), 7.69 (t, J_(HF)=71.53 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 2.71 (s,3H), 1.62 (s, 9H); LC-MS: Method A, 50 to 100% B. RT=2.00 min, MS (ESI)m/z: 459.0 (M+H)⁺. Analytical HPLC (method A): Sunfire, RT=11.9 min,100% purity; XBridge, RT=7.46 min, 97% purity.

Example 152-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(thiazol-4-ylmethoxy)benzo[d]thiazo

Intermediate 15A: 2-bromo-3-methoxyaniline

To a suspension of 2-bromo-1-methoxy-3-nitrobenzene (3.90 g, 16.81 mmol)and iron powder (2.82 g, 50.4 mmol) in EtOH (50 mL) was addedconcentrated HCl (3.08 mL, 37.0 mmol). The mixture was heated at 85° C.for 2.0 h. HPLC indicated a completion of the reaction. After cooled toroom temperature, the solvent was removed under vacuum. The residue wassuspended in EtOAc and saturated sodium bicarbonate. The insolublematerial was removed by filtration through a pad of wet celite. Theorganic layer of the filtrate was collected, washed with brine, driedover sodium sulfate. After evaporation of solvent, Intermediate 15A(3.25 g, 16.09 mmol, 96% yield) was obtained as brown oil. It was usedfor the next step without further purification. ¹H NMR (500 MHz,chloroform-d) δ 7.08 (t, J=8.1 Hz, 1H), 6.45 (dd, J=8.0, 1.4 Hz, 1H),6.34 (dd, J=8.3, 1.1 Hz, 1H), 3.89 (s, 2H); LC-MS: method A, RT=1.21min, MS (ESI) m/z: 202.0 and 204.0 (M+H)⁺.

Intermediate 15B: 7-methoxybenzo[d]thiazole-2-thiol

A solution of Intermediate 15A (3.25 g, 16.09 mmol) and potassiumO-ethyl carbonodithioate (6.45 g, 40.2 mmol) in DMF (20 mL) was heatedat 135° C. under argon for 6.0 h. HPLC and LCMS indicated a completionof the reaction. The mixture was cooled to room temperature, dilutedwith 20 mL water, followed by addition of 30 mL 1.0 N HCl. Theprecipitate formed was collected by filtration, washed with water, driedunder vacuum and then chased with toluene (3×) to yield Intermediate 15B(3.1 g, 15.71 mmol, 98% yield) as a brown solid. It was used for thenext step without further purification. ¹H NMR (500 MHz, DMSO-d₆) δ13.77 (br. s., 1H), 7.38 (t, J=8.1 Hz, 1H), 6.94 (t, J=8.1 Hz, 2H), 3.91(s, 3H); LC-MS: method A, RT=1.63 min, MS (ESI) m/z: 198.0 (M+H)⁺.

Intermediate 15C: 7-methoxy-2-(methylthio)benzo[d]thiazole

To a solution of Intermediate 15B (2.01 g, 10.19 mmol) in DMF (40 mL) atroom temperature was added potassium carbonate (3.52 g, 25.5 mmol).After stirring at room temperature for 10 min, iodomethane (0.796 mL,12.74 mmol) was added. The reaction mixture was stirred at roomtemperature for 20 min, at which time HPLC indicated a completion of thereaction. It was diluted with EtOAc, washed with water, brine and driedover sodium sulfate. After evaporation of solvent, Intermediate 15C (2.2g, 10.41 mmol, 102% yield) was obtained as a brown solid. It was usedfor the next step without purification. ¹H NMR (500 MHz, chloroform-d) δ7.53 (dd, J=8.0, 0.8 Hz, 1H), 7.39 (t, J=8.1 Hz, 1H), 6.79 (dd, J=8.0,0.6 Hz, 1H), 3.99 (s, 3H), 2.82 (s, 3H); LC-MS: method A, RT=2.00 min,MS (ESI) m/z: 212.0 (M+H)⁺.

Intermediate 15D: 7-methoxy-2-(methylsulfonyl)benzo[d]thiazole

To a solution of Intermediate 15C (2.2 g, 10.41 mmol) dissolved in MeOH(100 mL) was added dropwise a solution of OXONE (19.20 g, 31.2 mmol)suspended in water (100 mL). The reaction mixture was stirred at roomtemperature over the weekend. HPLC and TLC indicated a completion of thereaction. The reaction was quenched by addition of dimethyl sulfide(4.62 mL, 62.5 mmol). After stirring at room temperature for 45 min,methanol was removed under vacuum. The mixture was diluted withEtOAc/water. The insoluble material was removed by filtration. Thefiltrate was collected. The organic layer was washed with water (2×),saturated sodium bicarbonate, brine and dried over sodium sulfate. Afterevaporation of solvent, Intermediate 15D (2.5 g, 10.28 mmol, 99% yield)was obtained as a pale solid. ¹H NMR (500 MHz, chloroform-d) δ 7.83 (dd,J=8.3, 0.8 Hz, 1H), 7.59 (t, J=8.1 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 4.05(s, 3H), 3.42 (s, 3H); LC-MS: method A, RT=1.55 min, MS (ESI) m/z: 243.9(M+H)⁺.

Intermediate 15E: 2-hydrazinyl-7-methoxybenzo[d]thiazole

To a suspension of Intermediate 15D (2.5 g, 10.28 mmol) in EtOH (15 mL)was added hydrazine monohydrate (15.55 mL, 308 mmol). The mixture wassonicated for 2 min, heated in oil bath at 100° C. for 1.0 h. HPLC andLCMS indicated a completion of the reaction. Solvent was removed undervacuum. The crude was redissolved in MeOH, and MeOH was removed undervacuum. To the crude was then added ice-cold water (6.0 mL). Theprecipitate formed was collected by filtration, washed with water, driedover air for 30 min and then at high vacuum over night to giveIntermediate 15E (1.67 g, 8.55 mmol, 83% yield) as a pale yellow solid.¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.97(dd, J=8.0, 0.8 Hz, 1H), 6.64 (dd, J=8.3, 0.6 Hz, 1H), 5.01 (s, 2H),3.32 (s, 3H); LC-MS: method A, 0 to 100% B. RT=1.15 min, MS (ESI) m/z:196.0 (M+H)⁺.

Intermediate 15F: 2-chloro-7-methoxybenzo[d]thiazole

To Intermediate 15E (1.6 g, 8.19 mmol) suspended in dichloromethane (8.0mL) in a round-bottom flask was added thionyl chloride (8.37 mL, 115mmol) slowly. The reaction mixture was heated in a pre-heated oil bathat 55° C. for 30 min. HPLC indicated a completion of the reaction.Thionyl chloride was removed under vacuum, chased with EtOAc once togive a yellow solid. The solid was dissolved in EtOAc, washed withsaturated sodium bicarbonate, brine, dried over sodium sulfate. Afterevaporation of solvent, Intermediate 15F (1.6 g, 8.01 mmol, 98% yield)was obtained as yellow solid. It was used for the next step withoutfurther purification. ¹H NMR (400 MHz, chloroform-d) δ 7.53-7.48 (m,1H), 7.36 (t, J=8.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 3.91 (s, 3H);LC-MS: method A, RT=1.98 min, MS (ESI) m/z: 199.9 201.9 (M+H)⁺.

Intermediate 15G: 2-chlorobenzo[d]thiazol-7-ol

Aluminum chloride (2.67 g, 20.03 mmol) was added to a solution ofIntermediate 15F (1.6 g, 8.01 mmol) in toluene (40 mL). The mixture washeated at 85° C. for 1.5 h. HPLC indicated a complete conversion ofstarting material. The reaction mixture was cooled to room temperature,quenched with ice-cold 1.0 N HCl (30 mL) and EtOAc (50 mL), and stirredat room temperature for 30 min. The organic layer was collected, washedwith water, saturated sodium bicarbonate, brine and dried over sodiumsulfate. After evaporation of solvent, the crude product was trituratedwith EtOAc/hexanes (1:3). The precipitate was collected to giveIntermediate 15G (1.3 g). The filtrate was concentrated, dissolved in asmall amount of chloroform and charged to a 12 g silica gel cartridgewhich was eluted with 5% for 2 min., then a 12 min gradient from 5% to50%. The desired fractions were combined and concentrated to giveadditional product (96 mg). LC-MS: method A, RT=1.66 min, MS (ESI) m/z:186.0 and 188.0 (M+H)⁺.

Intermediate 15H:7-((tert-butyldimethylsilyl)oxy)-2-chlorobenzo[d]thiazole

To a stirred solution of Intermediate 15G (1.39 g, 7.49 mmol) in DMF (20mL) was added TBDMS-Cl (1.467 g, 9.73 mmol) and imidazole (0.892 g,13.10 mmol). The reaction mixture was left stirring at room temperaturefor 1.0 h. The mixture was partitioned between EtOAc/water. The organiclayer was washed with brine and dried over sodium sulfate. Afterevaporation of solvent, the crude product was dissolved in a smallamount of chloroform and charged to a 40 g silica gel cartridge whichwas eluted with hexanes for 3 min., then a Intermediate 15 min gradientfrom 0% to 15%. The desired fractions were combined and concentrated togive Intermediate 15H (2.14 g, 7.14 mmol, 95% yield) as brown oil. ¹HNMR (500 MHz, chloroform-d) δ 7.60 (dd, J=8.3, 0.8 Hz, 1H), 7.37 (t,J=8.1 Hz, 1H), 6.85 (dd, J=8.0, 0.8 Hz, 1H), 1.07 (s, 9H), 0.29 (s, 6H);LC-MS: Method A, 50 to 100% B. RT=2.38 min, MS (ESI) m/z: 300.0 and302.0 (M+H)⁺.

Intermediate 15I7-((tert-butyldimethylsilyl)oxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole

To Intermediate I-1 (1.05 g, 3.12 mmol), Intermediate 15H (1.077 g, 3.59mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex with dichloromethane (1:1) (0.128 g, 0.156 mmol) was addedtoluene (9 mL), EtOH (3 mL) and sodium carbonate (2M, 3.12 mL, 6.25mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 135° C. for 70 min. HPLCindicated completion of reaction. To the reaction mixture was addedEtOAc/water/brine. The insoluble was removed by filtration with a pad ofcelite. The organic layer was collected, washed with brine, dried oversodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of toluene/chloroform and charged to a 80 gsilica gel cartridge which was eluted with hexanes for 3 min., then a 20min gradient from 0% to 75%. The desired fractions were combined andconcentrated to give Intermediate 15I (0.98 g, 2.069 mmol, 66.2% yield)as a bright yellow solid. ¹H NMR (500 MHz, chloroform-d) δ 8.81 (d,J=1.9 Hz, 1H), 8.76 (s, 1H), 7.83-7.80 (m, 2H), 7.68 (t, J_(HF)=71.80Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.86 (dd, J=7.8, 0.7 Hz, 1H), 2.71 (s,3H), 1.13 (s, 9H), 0.35 (s, 6H); ¹⁹F NMR (471 MHz, chloroform-d) δ−89.74 (s, 2F); LC-MS: Method A, 80 to 100% B. RT=2.41 min, MS (ESI)m/z: 474.0 (M+H)⁺.

Intermediate 15J:2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-ol

To a solution of Intermediate 15I (1.96 g, 4.14 mmol) in THF (15 mL) atroom temperature was added acetic acid (0.521 mL, 9.10 mmol), followedby addition of 1.0 N TBAF in THF (4.97 mL, 4.97 mmol) dropwise. Thereaction mixture was stirred at room temperature for 20 min, at whichtime HPLC and LCMS indicated a completion of the reaction. The mixturewas diluted with EtOAc, washed with water, saturated sodium bicarbonate(2×), brine, and dried over sodium sulfate. After evaporation of thesolvent, the crude product was triturated with EtOAc/hexanes (1:4). Theprecipitate was collected by filtration to give Intermediate 15J (1.40g, 3.893 mmol, 94.0% yield). The filtrate was further concentrated andpurified with a 12 g ISCO column eluting with 5%-50% EtOAc in hexanesover 12 min. to give additional product (60 mg). ¹H NMR (500 MHz,methanol-d₄) δ 8.78 (s, 1H), 8.72 (d, J=1.9 Hz, 1H), 7.87 (s, 1H), 7.79(t, J_(HF)=71.80 Hz, 1H), 7.60 (dd, J=8.3, 0.6 Hz, 1H), 7.38 (t, J=8.0Hz, 1H), 6.84 (dd, J=7.7, 0.6 Hz, 1H), 2.70 (s, 3H); ¹⁹F NMR (471 MHz,methanol-d₄) δ −91.07 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=1.68min, MS (ESI) m/z: 360.0 (M+H)⁺.

Example 15

A solution of 4-hydroxymethyl thiazole (24.03 mg, 0.209 mmol) and DIAD(0.041 mL, 0.209 mmol) in THF (1.0 mL) was added dropwise to a mixtureof Intermediate 15J (25 mg, 0.070 mmol) and triphenylphosphine (36.5 mg,0.139 mmol) in THF (0.5 mL) heated at 65° C. At the end of addition,HPLC and LCMS indicated a complete conversion of starting material tothe product. Solvent was removed under vacuum and the crude wasdissolved in DMSO/acetonitrile (2 mL/1 mL), filtered and purified byprep HPLC (method A, 65-100% B in 10 min; RT=7.2 min). The desiredfractions were placed in a SpeedVac overnight to remove solvent, thenlyophilized to give Example 15 (10 mg, 0.022 mmol, 31.2% yield) asyellow lyophilate. ¹H NMR (500 MHz, chloroform-d) δ 8.94 (d, J=2.2 Hz,1H), 8.85 (d, J=1.7 Hz, 1H), 8.74 (s, 1H), 7.86-7.82 (m, 2H), 7.69 (t,J_(HF)=71.53 Hz, 1H), 7.59-7.56 (m, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.00(d, J=7.7 Hz, 1H), 5.57 (d, J=0.6 Hz, 2H), 2.71 (s, 3H); ¹⁹F NMR (471MHz, chloroform-d) δ −89.74 (s, 2F); LC-MS: Method A, 50 to 100% B.RT=1.94 min, MS (ESI) m/z: 457.0 (M+H)⁺. Analytical HPLC (method A):Sunfire, RT=11.07 min, 99% purity; XBridge, RT=7.14 min, 99% purity.

Example 16 tetrahydrofuran-3-yl(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate

To a stirred solution of THF-3-ol (8.21 mg, 0.093 mmol) indichloromethane (0.6 mL) was added 20% phosgene in toluene (0.078 mL,0.149 mmol). The reaction mixture was stirred at room temperature for1.5 h. Solvent was removed under vacuum. The chloroformate obtained wasdissolved in dichloromethane (0.5 mL) and added to a solution ofIntermediate I-4 (15 mg, 0.037 mmol) and TEA (0.026 mL, 0.186 mmol) indichloromethane (0.6 mL). The reaction mixture was stirred at roomtemperature for 30 min. Solvent was removed under vacuum. The crude wasdissolved in acetonitrile/DMSO (1 mL/0.5 mL) and was purified by prepHPLC (method A, 60-100% B in 10 min; RT=6 min). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto give Example 16 (3.0 mg, 5.69 μmol, 15.27% yield). ¹H NMR (500 MHz,chloroform-d) δ 8.76 (d, J=1.9 Hz, 1H), 8.71 (s, 1H), 8.09 (d, J=8.8 Hz,1H), 7.84 (dd, J=1.9, 0.8 Hz, 1H), 7.68 (t, J_(HF)=71.53 Hz, 1H), 7.43(d, J=2.5 Hz, 1H), 7.17 (dd, J=9.1, 2.5 Hz, 1H), 5.35-5.24 (m, 2H), 4.18(t, J=5.0 Hz, 2H), 3.99-3.86 (m, 3H), 3.69 (q, J=5.0 Hz, 2H), 2.71 (s,3H), 2.20 (dd, J=14.2, 6.2 Hz, 1H), 2.11-2.04 (m, 1H); ¹⁹F NMR (471 MHz,chloroform-d) δ −89.77 (s, 2F); LC-MS: method A, RT=2.31 min, MS (ESI)m/z: 517.0 (M+H)⁺. Analytical HPLC (method A): Sunfire, RT=8.80 min, 98%purity; XBridge, RT=5.64 min, 98% purity.

Example 172-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-phenoxyethoxy)benzo[d]thiazole

A solution of 2-phenoxyethanol (20.76 mg, 0.150 mmol) and DIAD (0.029mL, 0.150 mmol) in THF (1.0 mL) was added dropwise to a mixture ofIntermediate 15J (18 mg, 0.050 mmol) and triphenylphosphine (26.3 mg,0.100 mmol) in THF (0.5 mL) heated at 65° C. At the end of addition,HPLC and LCMS indicated a complete conversion of starting material tothe product. Solvent was removed under vacuum and the crude wasdissolved in DMSO/acetonitrile (1 mL/1 mL), filtered and purified byprep HPLC (method A, 80-100% B in 10 min; RT=8 min). The desiredfractions were placed in a SpeedVac overnight to remove solvent, thenlyophilized to give Example 17 (13 mg, 0.026 mmol, 52.5% yield) asyellow lyophilate. ¹H NMR (500 MHz, methanol-d₄) δ 8.66 (d, J=1.7 Hz,1H), 8.62 (s, 1H), 7.73 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.57 (t,J_(HF)=71.80 Hz, 1H), 7.39 (t, J=8.1 Hz, 1H), 7.24 (t, J=8.0 Hz, 2H),6.95-6.89 (m, 3H), 6.85 (d, J=8.0 Hz, 1H), 4.51-4.47 (m, 2H), 4.41-4.36(m, 2H), 2.59 (s, 3H); ¹⁹F NMR (471 MHz, methanol-d₄) δ −93.93 (s, 2F);LC-MS: Method A, 50 to 100% B. RT=2.35 min, MS (ESI) m/z: 480.0 (M+H)⁺.Analytical HPLC (method A): Sunfire, RT=5.27 min, 97% purity; XBridge,RT=2.99 min, 97% purity.

Example 187-(2-(benzyloxy)ethoxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole

A solution of 2-(benzyloxy)ethanol (22.87 mg, 0.150 mmol) and DIAD(0.029 mL, 0.150 mmol) in THF (1.0 mL) was added dropwise to a mixtureof Intermediate 15J (18 mg, 0.050 mmol) and triphenylphosphine (26.3 mg,0.100 mmol) in THF (0.5 mL) heated at 65° C. At the end of addition,HPLC and LCMS indicated a complete conversion of starting material tothe product. Solvent was removed under vacuum and the crude wasdissolved in DMSO/acetonitrile (1 mL/1 mL), filtered and purified byprep HPLC (method A, 65-100% B in 10 min; RT=7.2 min). The desiredfractions were placed in a SpeedVac overnight to remove solvent, thenlyophilized to give Example 18 (5.0 mg, 9.83 μmol, 19.62% yield) asyellow lyophilate. ¹H NMR (500 MHz, chloroform-d) δ 8.87 (d, J=1.9 Hz,1H), 8.74 (s, 1H), 7.84 (dd, J=2.2, 1.1 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H),7.69 (t, J_(HF)=71.80 Hz, 1H), 7.50-7.45 (m, 3H), 7.44-7.39 (m, 2H),7.36-7.32 (m, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.75 (s, 2H), 4.47-4.42 (m,2H), 4.03-3.98 (m, 2H), 2.72 (s, 3H); ¹⁹F NMR (471 MHz, chloroform-d) δ−89.74 (s, 2F); LC-MS: Method A, 50 to 100% B. RT=2.33 min, MS (ESI)m/z: 494.0 (M+H)⁺. Analytical HPLC (method A): Sunfire, RT=5.58 min, 96%purity; XBridge, RT=3.01 min, 98% purity.

Example 19 (Tetrahydrofuran-2-yl)methyl(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate

To a solution of (THF-2-yl)methanol (0.194 mL, 1.997 mmol) indichloromethane (2.0 mL) was added phosgene, 20% in toluene (3.15 mL,5.99 mmol). The reaction mixture was stirred at room temperature for 18h. Solvent was removed under vacuum to give the chloroformate (0.32 g,1.944 mmol, 97% yield) as a colorless liquid that was used for the nextstep without further purification.

To a solution of Intermediate I-4 (15 mg, 0.037 mmol) in dichloromethane(0.5 mL) was added DIEA (0.052 mL, 0.298 mmol). After stirring at roomtemperature for 5 min, the chloroformate obtained above (18.40 mg, 0.112mmol) was added. The reaction mixture was stirred at room temperaturefor 15 min. HPLC and LCMS indicated a completion of the reaction.Solvent was removed under vacuum. The crude was dissolved inacetonitrile/DMSO (1 mL/1.0 mL) and was purified by prep HPLC (method A,60-100% B in 10 min; RT=6.5 min). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to give Example19 (14 mg, 0.026 mmol, 68.7% yield) as yellow lyophilate. ¹H NMR (500MHz, chloroform-d) δ 8.73 (d, J=1.9 Hz, 1H), 8.67 (s, 1H), 8.09 (d,J=9.1 Hz, 1H), 7.82 (dd, J=1.9, 1.1 Hz, 1H), 7.67 (t, J_(HF)=71.80 Hz,1H), 7.39 (d, J=1.9 Hz, 1H), 7.16 (dd, J=8.9, 2.3 Hz, 1H), 5.40 (br. s.,1H), 4.25 (dd, J=11.3, 3.0 Hz, 1H), 4.19-4.15 (m, 3H), 4.03 (dd, J=11.1,7.6 Hz, 1H), 3.96-3.90 (m, 1H), 3.88-3.82 (m, 1H), 3.69 (q, J=5.4 Hz,2H), 2.69 (s, 3H), 2.07-2.00 (m, 1H), 1.99-1.91 (m, 2H); ¹⁹F NMR (471MHz, chloroform-d) δ −89.77 (s, 2F); LC-MS: Method A, 50 to 100% B.RT=1.88 min, MS (ESI) m/z: 531.0 (M+H)⁺. Analytical HPLC (method A):Sunfire, RT=4.06 min, 97% purity; XBridge, RT=3.02 min, 97% purity.

Example 20 tetrahydro-2H-pyran-4-yl(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate

To a solution of tetrahydro-2H-pyran-4-ol (0.196 mL, 2.056 mmol) and indichloromethane (2.0 mL) was added phosgene, 20% in toluene (3.25 mL,6.17 mmol). The reaction mixture was stirred at room temperature for 18h. Solvent was removed under vacuum to give the chloroformate (0.33 g,2.005 mmol, 98% yield) as a colorless liquid that was used for the nextstep without further purification.

To a solution of Intermediate I-4 (15 mg, 0.037 mmol) in dichloromethane(0.5 mL) was added DIEA (0.052 mL, 0.298 mmol). After stirring at roomtemperature for 5 min, the chloroformate (18.40 mg, 0.112 mmol) wasadded. The reaction mixture was stirred at room temperature for 15 min.HPLC and LCMS indicated a completion of the reaction. Solvent wasremoved under vacuum. The crude was dissolved in acetonitrile/DMSO (1mL/1.0 mL) and was purified by prep HPLC (method A, 60-100% B in 10 min;RT=6.5 min). The desired fractions were placed in a SpeedVac overnightto remove solvent, then lyophilized to give Example 20 (4.0 mg, 7.39μmol, 19.82% yield) as yellow lyophilate. ¹H NMR (500 MHz, chloroform-d)δ 8.78 (d, J=1.7 Hz, 1H), 8.71 (s, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.84(dd, J=1.8, 1.0 Hz, 1H), 7.67 (t, J_(HF)=71.80 Hz, 1H), 7.44 (d, J=2.5Hz, 1H), 7.19 (dd, J=8.8, 2.5 Hz, 1H), 5.24 (br. s., 1H), 4.91 (br. s.,1H), 4.19 (t, J=5.1 Hz, 3H), 3.99-3.93 (m, 4H), 3.70 (q, J=5.3 Hz, 3H),3.58 (t, J=9.5 Hz, 3H), 2.71 (s, 3H), 1.98 (d, J=10.7 Hz, 2H), 1.76-1.68(m, 2H); ¹⁹F NMR (471 MHz, chloroform-d) δ −89.78 (s, 2F); LC-MS: MethodA, 50 to 100% B. RT=1.86 min, MS (ESI) m/z: 531.0 (M+H)⁺. AnalyticalHPLC (method A): Sunfire, RT=4.09 min, 97% purity; XBridge, RT=3.04 min,98% purity.

Example 21 tetrahydro-2H-pyran-4-yl(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)carbamate

Intermediate 21A2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-amine

To a suspension of Example 14 (90 mg, 0.196 mmol) in ethyl acetate (1.0mL) and MeOH (1.0 mL) was added 4.0 N HCl in dioxane (2.454 mL, 9.82mmol). The reaction mixture was stirred at room temperature overnight.After evaporation of solvent, the crude residue was purified using apreparative HPLC (method A, 50-100% B in 10 min; RT=6 min). The desiredfractions were placed in a SpeedVac overnight to remove solvent. TFA wasremoved by redissolving in EtOAc and washing with saturated sodiumbicarbonate. After evaporation of solvent and lyophilization,Intermediate 21A (47 mg, 0.125 mmol, 63.5% yield) was obtained as yellowlyophilate. ¹H NMR (500 MHz, chloroform-d) δ 8.84 (s, 1H), 8.70 (s, 1H),7.81 (s, 1H), 7.66 (t, J_(HF)=71.80 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H),7.36 (t, J=7.8 Hz, 1H), 6.75 (d, J=7.7 Hz, 1H), 2.69 (s, 3H); LC-MS:Method A, 40 to 100% B. RT=1.60 min, MS (ESI) m/z: 359.0 (M+H)⁺.Analytical HPLC (method A): Sunfire, RT=5.54 min, 95% purity; XBridge,RT=4.54 min, 95% purity.

Example 21

To a solution of Intermediate 21A (15 mg, 0.042 mmol) in THF (0.8 mL)was added TEA (0.035 mL, 0.251 mmol). After stirring at room temperaturefor 2 min, the chloroformate prepared in Example 20 (20.67 mg, 0.126mmol) was added. The reaction mixture was stirred at 50° C. for 1.0 h.HPLC and LCMS indicated a completion of the reaction. The reactionmixture was quenched with 1.0 N HCl (0.25 mL). Solvent was removed undervacuum. The crude was purified via preparative LC/MS (method D, 40-75% Bover 10 minutes). Fractions containing the desired product were combinedand dried via centrifugal evaporation to give Example 21 (8 mg). ¹H NMR(500 MHz, methanol-d₄) δ 8.72 (s, 2H), 7.92 (d, J=8.5 Hz, 1H), 7.85 (d,J=1.9 Hz, 1H), 7.71 (t, J_(HF)=71.53 Hz, 1H), 7.58-7.53 (m, 1H),7.53-7.48 (m, 1H), 5.01 (dt, J=8.4, 4.3 Hz, 1H), 4.25 (s, 2H), 3.98 (br.s., 2H), 3.66-3.59 (m, 1H), 2.69 (s, 3H), 2.08 (dd, J=9.1, 4.1 Hz, 1H),1.83 (ddt, J=13.2, 8.8, 4.3 Hz, 1H); LC-MS: method A, RT=2.18 min, MS(ESI) m/z: 487.2 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 22 (Tetrahydrofuran-2-yl)methyl(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)carbamate

To a solution of Intermediate 21A (15 mg, 0.042 mmol) in THF (0.5 mL)was added TEA (0.035 mL, 0.251 mmol). After stirring at room temperaturefor 2 min, the chloroformate prepared in Example 19 (15.16 mg, 0.092mmol) was added. The reaction mixture was stirred at room temperaturefor 45 min. The reaction mixture was quenched with 1.0 N HCl (0.25 mL).Solvent was removed under vacuum. The crude was purified via preparativeLC/MS (method D, 40-75% B over 13 minutes). Fractions containing thedesired product were combined and dried via centrifugal evaporation toyield Example 22 (9 mg). ¹H NMR (500 MHz, methanol-d₄) δ 8.73 (d, J=1.9Hz, 1H), 8.71 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 7.71 (t,J_(HF)=71.53 Hz, 1H), 7.57 (d, J=10.7 Hz, 1H), 7.53-7.48 (m, 1H), 4.31(dd, J=11.3, 3.3 Hz, 1H), 4.28-4.22 (m, 1H), 4.17-4.11 (m, 1H), 3.94(br. s., 1H), 3.86 (d, J=7.2 Hz, 1H), 2.69 (s, 3H), 2.10 (dd, J=12.1,5.8 Hz, 1H), 1.98 (d, J=7.2 Hz, 2H), 1.78-1.69 (m, 1H); LC-MS: method A,RT=2.18 min, MS (ESI) m/z: 487.3 (M+H)⁺. Analytical HPLC purity (methodB): 100%.

Example 232-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methoxythiazolo[5,4-b]pyridine

Intermediate 23A: 5-methoxythiazolo[5,4-b]pyridin-2-amine

To 6-methoxypyridin-3-amine (636 mg, 5.12 mmol) in acetonitrile (14 mL)was added ammonium thiocyanate (585 mg, 7.68 mmol). The reaction mixturewas stirred at room temperature for 10 min. Then benzyltrimethylammoniumtribromide (1998 mg, 5.12 mmol) in acetonitrile (5.0 mL) was addeddropwise (10 min). The mixture was then stirred at room temperatureovernight. HPLC and LCMS indicated a single major peak with the desiredmass. The mixture was diluted with EtOAc/saturated sodium bicarbonate.The organic layer was collected, washed with saturated sodiumbicarbonate, brine, dried over sodium sulfate. After evaporation ofsolvent, Intermediate 23A (900 mg, 4.97 mmol, 97% yield) was obtained asa brown solid. ¹H NMR indicated >90% purity. It was used for the nextstep without further purification. ¹H NMR (500 MHz, DMSO-d₆) δ 7.61 (d,J=8.5 Hz, 1H), 7.41 (s, 2H), 6.69 (d, J=8.5 Hz, 1H), 3.83 (s, 3H);LC-MS: method A, RT=1.08 min, MS (ESI) m/z: 181.9 (M+H)⁺.

Intermediate 23B: 2-bromo-5-methoxythiazolo[5,4-b]pyridine

Tert-butyl nitrite (0.175 mL, 1.324 mmol) was added to copper (II)bromide (266 mg, 1.192 mmol) in dry acetonitrile (5 mL) under argon. Thereaction mixture was stirred at room temperature for 10 min.Intermediate 23A (160 mg, 0.883 mmol) was added. The reaction mixturewas stirred at room temperature for 4.0 h. HPLC and LCMS indicated acompletion of the reaction. Acetonitrile was removed under vacuum, thereaction mixture was diluted with EtOAc, quenched with 0.5N HCl. Afterstirring at room temperature for 10 min, some insoluble impurity wasremoved by filtration through a pad of wet celite. The organic layer ofthe filtrate was collected, washed with saturated sodium bicarbonate,brine and dried over sodium sulfate. The crude product was purified byflash chromatography (loading in chloroform, 0% to 30% EtOAc in hexaneover 15 min using a 12 g silica gel cartridge). The desired fractionswere combined and concentrated to yield Intermediate 23B (194 mg, 0.792mmol, 90% yield) as yellow solid. ¹H NMR (500 MHz, chloroform-d) δ 8.08(d, J=8.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 4.02 (s, 3H); LC-MS: methodA, RT=1.92 min, MS (ESI) m/z: 244.8 and 246.8 (M+H)⁺.

Example 23

To Intermediate I-1 (25 mg, 0.074 mmol), Intermediate 23B (22.79 mg,0.093 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (3.04 mg, 3.72 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.082mL, 0.164 mmol). The reaction mixture was heated in a microwave reactorat 130° C. for 30 min. After cooled to room temperature, it was dilutedwith EtOAc, washed with saturated sodium bicarbonate, brine. The organiclayer was dried over sodium sulfate, concentrated and purified viapreparative LC/MS (method D, 50-90% B over 10 minutes, then a 5-minutehold at 100% B). Fractions containing the desired product were combinedand dried via centrifugal evaporation to yield Example 23 (8.0 mg). ¹HNMR (500 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.71 (s, 1H), 8.40 (d, J=8.8 Hz,1H), 7.93 (s, 1H), 7.89 (t, J_(HF)=71.25 Hz, 1H), 7.06 (d, J=9.1 Hz,1H), 4.01 (s, 3H), 2.68 (s, 3H); LC-MS: method A, RT=2.39 min, MS (ESI)m/z: 375.0 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 242-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxythiazolo[4,5-c]pyridine

Intermediate 24A: 7-methoxythiazolo[4,5-c]pyridine-2-thiol

A solution of 4-chloro-5-methoxypyridin-3-amine (0.25 g, 1.576 mmol) andpotassium O-ethyl carbonodithioate (0.695 g, 4.34 mmol) in DMF (2) washeated at 135° C. under argon for 3.0 h. HPLC and LCMS indicated acompletion of the reaction. The mixture was cooled to room temperature,diluted with 2.0 mL water, followed by addition of 10 mL 1.0 N HCl. Theprecipitated formed was stirred at room temperature for 15 min, thencollected by filtration, washed with water, dried under vacuum and thenlyophilized to give Intermediate 24A (0.27 g, 1.362 mmol, 86% yield) asa brown solid. It was used for the next step without furtherpurification. ¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (s, 1H), 8.23 (s, 1H),4.02 (s, 3H); LC-MS: method A, RT=1.20 min, MS (ESI) m/z: 198.9 (M+H)⁺.

Intermediate 24B: 2-chloro-7-methoxythiazolo[4,5-c]pyridine

To a slurry of Intermediate 24A (60 mg, 0.303 mmol) in dichloromethane(0.3 mL) was added sulfuryl chloride (0.492 mL, 6.05 mmol). Thesuspension was stirred at room temperature overnight. To the yellowsuspension was added ice/water, stirred at room temperature for 15 minto decompose the excess sulfuryl chloride (exothermic!). EtOAc and 4.0 NNaOH were added to adjust the pH to 10-12. The organic layer wascollected, washed with brine, dried over sodium sulfate. Afterevaporation of solvent, the crude product was dissolved in a smallamount of chloroform and charged to a 4 g silica gel cartridge which waseluted with 5% EtOAc in hexanes for 2 min., then a 10 min gradient from5% to 60%. The desired fractions were combined and concentrated to giveIntermediate 24B (40 mg, 0.199 mmol, 65.9% yield) as a white solid. ¹HNMR (500 MHz, chloroform-d) δ 8.95 (s, 1H), 8.24 (s, 1H), 4.11 (s, 3H);LC-MS: method A, RT=1.21 min, MS (ESI) m/z: 200.9 and 202.9 (M+H)⁺.

Example 24

To Intermediate I-1 (30 mg, 0.089 mmol), Intermediate 24B (22.38 mg,0.112 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (3.64 mg, 4.46 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.098mL, 0.196 mmol). The reaction mixture was heated in a microwave reactorat 130° C. for 30 min. After cooled to room temperature, it was dilutedwith EtOAc, washed with saturated sodium bicarbonate, brine. The organiclayer was dried over sodium sulfate, concentrated and purified viapreparative LC/MS (method D, 35-80% B over 10 minutes, then a

After a five-minute hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to yieldExample 24 (4.1 mg). ¹H NMR (400 MHz, acetonitrile-d₃) δ 9.23 (s, 1H),8.91 (s, 1H), 8.86 (s, 1H), 8.32 (s, 1H), 8.00 (s, 1H), 7.73 (t,J_(HF)=71.50 Hz, 1H), 4.24 (s, 3H); ¹⁹F NMR (376 MHz, acetonitrile-d₃) δ−77.11 (br. s., 3F, TFA), −90.66 (s, 2F); LC-MS: method A, RT=1.95 min,MS (ESI) m/z: 374.9 (M+H)⁺. Analytical HPLC purity (method B): 91%.

Example 25 tert-butyl(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzofuran-4-yl)carbamate

Intermediate 25A: 4,5,6,7-tetrahydrobenzofuran-4-ol

To a solution of 6,7-dihydrobenzofuran-4(5H)-one (4.94 g, 36.3 mmol) inMeOH (110 mL) at 0° C. was added NaBH₄ (1.579 g, 41.7 mmol) in 3portions. The reaction mixture was stirred at 0° C. for 2.0 h. TLCindicated a completion of the reaction. MeOH was removed under reducedpressure. To the residue was added EtOAc, water. The pH was adjusted to7 with saturated ammonium chloride/0.5 N HCl. The organic layer wascollected, washed with brine, dried over sodium sulfate. Afterevaporation of solvent, Intermediate 25A (4.96 g, 35.9 mmol, 99% yield)was obtained as a clear oil. ¹H NMR (500 MHz, chloroform-d) δ 7.29-7.26(d, J=1.77 Hz, 1H), 6.41 (d, J=1.77 Hz, 1H), 4.77-4.71 (m, 1H),2.69-2.61 (m, 1H), 2.59-2.50 (m, 1H), 2.04-1.89 (m, 2H), 1.87-1.75 (m,2H), 1.64 (br. s., 1H); LC-MS: method A, RT=1.24 min, MS (ESI) m/z: No(M+H)⁺.

Intermediate 25B:tert-butyldimethyl((4,5,6,7-tetrahydrobenzofuran-4-yl)oxy)silane

To a solution of Intermediate 25A (4.96 g, 35.9 mmol) in DMF (60 mL) wasadded imidazole (3.67 g, 53.8 mmol) and TBDMS-Cl (6.76 g, 44.9 mmol).The reaction mixture was stirred at room temperature for 1.5 h. TLC andHPLC indicated a completion of the reaction. The reaction mixture wasdiluted with EtOAc and quenched with water. The organic layer wascollected, washed with brine, dried over sodium sulfate and concentratedin vacuum. The crude product was purified by flash chromatography(loading in chloroform, 0% to 10% EtOAc in hexane over 20 min using a120 g silica gel cartridge). The desired fractions were combined andconcentrated to yield Intermediate 25B (8.34 g, 33.0 mmol, 92% yield) asa clear oil. ¹H NMR (500 MHz, chloroform-d) δ 7.27-7.25 (m, 1H), 6.33(d, J=1.9 Hz, 1H), 4.79-4.75 (m, 1H), 2.68-2.61 (m, 1H), 2.57-2.50 (m,1H), 2.10-2.02 (m, 1H), 1.95-1.89 (m, 1H), 1.81-1.68 (m, 2H), 0.95 (s,9H), 0.16 (s, 3H), 0.15 (s, 3H); LC-MS: Method A, 40 to 100% B. RT=2.30min, MS (ESI) m/z: No (M+H)⁺.

Intermediate 25C:tert-butyl((2-iodo-4,5,6,7-tetrahydrobenzofuran-4-yl)oxy) dimethylsilane

To Intermediate 25B (300 mg, 1.188 mmol) in THF (4.0 mL) at −78° C. wasadded 1.6 N n-BuLi in hexanes (1.114 mL, 1.783 mmol). The mixture waswarmed up to 0° C. with an ice bath and stirred for 20 min. The mixturewas cooled to −78° C. with dry ice/acetone bath, and iodine (362 mg,1.426 mmol) in 1 ml THF was added slowly, The reaction mixture wasstirred at −78° C. for 10 min, then at 0° C. for 30 min. The reactionmixture was diluted with EtOAc, quenched with saturated ammoniumchloride. The organic layer was washed with 10% Na₂S₂O₃, brine, driedover sodium sulfate. After evaporation of solvent, Intermediate 25C (414mg, 0.996 mmol, 84% yield) was obtained as a brown oil. ¹H NMRindicated >90% purity. It was used for next step without furtherpurification. ¹H NMR (500 MHz, chloroform-d) δ 6.47 (s, 1H), 4.74-4.70(m, 1H), 2.71-2.65 (m, 1H), 2.61-2.54 (m, 1H), 2.06-1.99 (m, 1H),1.92-1.86 (m, 1H), 1.77-1.64 (m, 2H), 0.95 (s, 9H), 0.15 (s, 3H), 0.14(s, 3H); LC-MS: Method A, 80 to 100% B. RT=1.76 min, MS (ESI) m/z: No(M+H)⁺.

Intermediate 25D5-(4-((tert-butyldimethylsilyl)oxy)-4,5,6,7-tetrahydrobenzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline

To Intermediate 25C (410 mg, 1.084 mmol) and Intermediate I-1 (335 mg,0.997 mmol) was added toluene (3 mL) and EtOH (1 mL). The reactionmixture was stirred at room temperature until solids are dissolved then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (35.4 mg, 0.043 mmol) was added. The flaskwas degassed and flushed with argon. Finally sodium carbonate (2M, 1.084mL, 2.167 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then put in microwave reactor at 130° C.for 30 min. To the reaction mixture was added EtOAc/water, stirred atroom temperature for 10 min. The insoluble material was removed byfiltration. The filtrate was extracted with EtOAc, washed with brine andconcentrated. The crude product was purified by flash chromatography(loading in chloroform, 0% to 15% EtOAc in hexane over 15 min using a 40g silica gel cartridge). The desired fractions were combined andconcentrated to yield Intermediate 25D (320 mg, 0.591 mmol, 54.5%yield): LC-MS: Method A, 80 to 100% B. RT=2.74 min, MS (ESI) m/z: 461.22(M+H)⁺.

Intermediate 25E2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzofuran-4-ol

To a solution of Intermediate 25D (320 mg, 0.695 mmol) in THF (2.0 mL)at room temperature was added 1.0 N TBAF in THF (0.834 mL, 0.834 mmol).The reaction mixture was stirred at room temperature for 4.0 h. HPLCindicated a completion of reaction. The mixture was diluted with EtOAc,washed with saturated sodium bicarbonate, brine, dried over sodiumsulfate and concentrated. The crude product was purified by flashchromatography (loading in chloroform, 0% to 30% EtOAc in hexane over 12min using a 12 g silica gel cartridge). The desired fractions werecombined and concentrated to yield Intermediate 25E (80 mg, 0.226 mmol,32.6% yield). ¹H NMR (500 MHz, methanol-d₄) δ 8.57 (s, 1H), 7.97 (d,J=1.7 Hz, 1H), 7.67 (t, J_(HF)=71.28 Hz, 1H), 7.67 (s, 1H), 7.53 (s,1H), 4.78 (t, J=4.7 Hz, 1H), 2.81-2.74 (m, 1H), 2.72-2.64 (m, 1H), 2.59(s, 3H), 2.14-2.07 (m, 1H), 2.02-1.95 (m, 1H), 1.91-1.77 (m, 2H); LC-MS:method A, RT=2.13 min, MS (ESI) m/z: 347.3 (M+H)⁺.

Intermediate 25F: tert-butylN-[(tert-butoxy)carbonyl]-N-{2-[2-(difluoromethoxy)-7-methylquinoxalin-5-yl]-4,5,6,7-tetrahydro-1-benzofuran-4-yl}carbamate

A solution of Intermediate 25E (74 mg, 0.214 mmol) and DIAD (0.091 mL,0.470 mmol) in THF (2.0 mL) was added dropwise to a mixture ofdi-tert-butyl iminodicarboxylate (81 mg, 0.374 mmol) andtriphenylphosphine (112 mg, 0.427 mmol) in THF (1.0 mL) heated at 50° C.At the end of addition, HPLC and LCMS indicated a complete conversion ofstarting material to the product. After evaporation of solvent, thecrude product was purified by flash chromatography (loading inchloroform, 0% to 30% EtOAc in hexanes over 18 min using a 12 g silicagel cartridge). The desired fractions were combined and concentrated toyield Intermediate 25F (12 mg, 0.022 mmol, 10.29% yield) as yellowsolid. ¹H NMR (500 MHz, chloroform-d) δ 8.58 (s, 1H), 7.98 (d, J=1.7 Hz,1H), 7.65 (t, J_(HF)=71.80 Hz, 1H), 7.56 (s, 1H), 7.52 (dd, J=1.8, 1.0Hz, 1H), 5.41-5.35 (m, 1H), 2.77-2.73 (m, 2H), 2.60 (s, 3H), 2.20-2.11(m, 4H), 1.47-1.44 (s, 18H); LC-MS: Method A, 50 to 100% B. RT=2.47 min,MS (ESI) m/z: 446.2 (M-Boc)⁺.

Example 25

To Intermediate 25F (12 mg, 0.022 mmol) was added dichloromethane (1.0mL) containing TFA (3.39 μl, 0.044 mmol). The solution was aged at roomtemperature overnight. Solvent was removed under vacuum. The crudematerial was purified via preparative LC/MS (method D, 55-95% B over 10minutes, then a 5-minute hold at 100% B). Fractions containing thedesired product were combined and dried via centrifugal evaporation toyield Example 25 (5.3 mg). ¹H NMR (500 MHz, methanol-d₄) δ 8.56 (s, 1H),7.96 (s, 1H), 7.66 (t, J_(HF)=72.80 Hz, 1H), 7.56-7.52 (m, 2H), 4.70(br. s., 1H), 2.75-2.68 (m, 2H), 2.58 (s, 3H), 2.03 (d, J=9.4 Hz, 2H),1.94-1.87 (m, 1H), 1.74 (dd, J=10.2, 6.3 Hz, 1H); LC-MS: method A,RT=2.59 min, MS (ESI) m/z: 468.3 (M+Na)⁺. Analytical HPLC purity (methodB): 100%.

Example 264-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Intermediate 26A: 2-chloro-6-methoxy-4-methylbenzo[d]thiazole

To a solution of copper (II) chloride (1.661 g, 12.35 mmol) inacetonitrile (8 mL) at 40° C. was added tert-butyl nitrite (1.769 mL,13.38 mmol), followed by Intermediate I-3A (2 g, 10.30 mmol) as a solid.The mixture was stirring at 40° C. for 2.0 h. HPLC and LCMS indicated acomplete conversion of starting material. The mixture was diluted withEtOAc, washed with 0.5 HCl, saturated sodium bicarbonate and brine.After evaporation of solvent, Intermediate 26A (2.4 g, 11.23 mmol, 99%yield) was obtained as a brown solid. ¹H NMR indicated >95% purity. ¹HNMR (500 MHz, chloroform-d) δ 7.07 (d, J=2.5 Hz, 1H), 6.93-6.77 (m, 1H),3.85 (s, 3H), 2.66 (s, 3H); LC-MS: method B, 0 to 100% B), retentiontime: 2.08 min, [M+1]⁺=213.9

Intermediate 26B: 2-chloro-4-methylbenzo[d]thiazol-6-ol

Aluminum chloride (4.49 g, 33.7 mmol) was added to a solution ofIntermediate 26A (2.4 g, 11.23 mmol) in toluene (50 mL). The mixture washeated at 110° C. for 1.5 h. TLC indicated a complete conversion ofstarting material. The reaction mixture was cooled to room temperature,quenched with ice-cold 1.0 N HCl (50 mL), stirred at room temperaturefor 30 min. The precipitate was collected by filtration, washed withwater (3×), saturated sodium bicarbonate (3×), water (3×) and air-driedfor 1.0 h under vacuum. It was further dried under high vacuum overnightto give Intermediate 26B as a brown solid (1.9 g). ¹H NMR (400 MHz,methanol-d₄) δ 7.06 (d, J=2.3 Hz, 1H), 6.82 (s, 1H), 2.57 (s, 3H).LC-MS: Method A, 50 to 100% B. RT=1.72 min, MS (ESI) m/z: 200.0 and202.0 (M+H)⁺.

Intermediate 26C:6-((tert-butyldimethylsilyl)oxy)-2-chloro-4-methylbenzo[d]thiazole

To a stirred solution of Intermediate 26B (2.2 g, 11.02 mmol) in DMF (50mL) was added TBDMS-Cl (2.325 g, 15.43 mmol) and imidazole (1.313 g,19.28 mmol). The reaction mixture was left stirring at room temperaturefor 1.0 h. HPLC and TLC indicated a completion of the reaction. Themixture was partitioned between EtOAc/water. The organic layer waswashed with brine and dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 120 g ISCO column which was eluted with hexanes for 3min., then a 30 min gradient from 0% to 50% EtOAc in hexanes. Thedesired fractions were combined and concentrated to give Intermediate26C (1.57 g, 5.00 mmol, 45.4% yield) as an orange solid. ¹H NMR (400MHz, chloroform-d) δ 7.09-6.94 (m, 1H), 6.81 (dd, J=2.5, 0.8 Hz, 1H),2.64 (s, 3H), 1.01 (s, 9H), 0.23 (s, 6H). LC-MS: Method A, 50 to 100% B.RT=2.72 min, MS (ESI) m/z: 314.0 and 316.0.0 (M+H)⁺.

Intermediate 26D6-((tert-butyldimethylsilyl)oxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole

To Intermediate I-1 (310 mg, 0.922 mmol), Intermediate 26C (333 mg,1.061 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (37.7 mg, 0.046 mmol) was addedtoluene (3 mL), EtOH (1 mL) and sodium carbonate (2M, 0.922 mL, 1.844mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 135° C. for 40 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layer was collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 12 g ISCO column which was eluted with hexanes for 3min., then a 20 min gradient from 0% to 75% EtOAc in hexanes. Thedesired fractions were combined and concentrated to yield Intermediate26D (450 mg, 0.923 mmol, 100% yield) as a bright yellow solid. LC-MS:Method A, 50 to 100% B. RT=2.72 min, MS (ESI) m/z: 488.0 (M+H)⁺.

Intermediate 26E:

2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol

To a solution of Intermediate 26D (450 mg, 0.923 mmol) in THF (5 mL) atroom temperature was added acetic acid (0.116 mL, 2.030 mmol), followedby addition of 1.0 N TBAF in THF (1.107 mL, 1.107 mmol) dropwise. Thereaction mixture was stirred at room temperature for 30 min. LCMSindicated a completion of reaction. The mixture was diluted with EtOAc,washed with water, saturated sodium bicarbonate (2×), brine, and driedover sodium sulfate. After evaporation of the solvent, the crude productwas purified with a 12 g ISCO column eluting from 5% EtOAc to 50% EtOAcin hexanes to give Intermediate 26E (290 mg, 0.777 mmol, 84% yield). ¹HNMR (500 MHz, acetonitrile-d₃) δ 8.81 (d, J=1.9 Hz, 1H), 8.74 (s, 1H),7.80 (dd, J=1.8, 1.0 Hz, 1H), 7.89-7.51 (m, 1H), 7.28 (d, J=1.9 Hz, 1H),6.88 (dd, J=2.5, 0.8 Hz, 1H), 2.76 (s, 3H), 2.69 (s, 3H). LC-MS: MethodA, 50 to 100% B. RT=1.44 min, MS (ESI) m/z: 373.9 (M+H)⁺.

Intermediate 26F2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanamine hydrochloride

A solution of DIAD (0.391 mL, 2.009 mmol) was added to a mixture ofIntermediate 26E (250 mg, 0.670 mmol). Tert-butyl(2-hydroxyethyl)carbamate (108 mg, 0.670 mmol) and triphenylphosphine(351 mg, 1.339 mmol) in toluene (5 mL) was added dropwise. The reactionmixture was heated 110° C. for 30 min. The mixture was concentrated anddissolved in 1 ml of DCM and purified by 40 g ISCO column eluted with0-70% EtOAc in hexanes for 20 min. The desired fraction wasconcentrated. The sample was redissolved in 5 ml of DCM and 4NHCl/dioxane (8.37 mL, 33.5 mmol) was added. The reaction mixture wasstirred at room temperature for 3 h. Solvent was removed under vacuum togive Intermediate 26F (250 mg, 0.552 mmol, 82% yield) as a solid. ¹H NMR(400 MHz, chloroform-d) δ 8.65 (d, J=1.8 Hz, 1H), 8.52 (s, 1H), 7.62 (d,J=0.8 Hz, 1H), 7.54 (t, J_(HF)=72 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 6.86(d, J=1.5 Hz, 1H), 5.02-4.95 (m, 2H), 3.98 (t, J=5.1 Hz, 2H), 2.72 (s,4H), 2.58 (s, 4H); LC-MS: Method A, 50 to 100% B. RT=2.12 min, MS (ESI)m/z: 416.9 (M+H)⁺.

Example 26

To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058mL, 0.331 mmol) in DMF (1 mL) was added a solution of4-fluorobenzene-1-sulfonyl chloride (7.73 mg, 0.040 mmol) in 0.2 ml ofDCM. The reaction mixture was stirred at room temperature for 1 h,diluted with EtOAc and water, extracted with EtOAc. The combined organiclayer was washed with brine, dried with MgSO₄ and concentrated. Thecrude sample was dissolved in 1 ml of MeOH and sodium methoxide (0.199mL, 0.099 mmol) was added. The reaction mixture was stirred at roomtemperature for 1h. The crude material was purified via preparativeLC/MS (method C, 45-85% B over 20 minutes, then a 5-minute hold at 100%B). Fractions containing the desired product were combined and dried viacentrifugal evaporation to yield Example 26 (7.0 mg). ¹H NMR (500 MHz,DMSO-d₆) δ 8.72 (s, 1H), 8.58 (s, 1H), 7.91 (dd, J=8.3, 5.5 Hz, 2H),7.81 (s, 1H), 7.46-7.41 (m, 3H), 6.86 (s, 1H), 4.09 (s, 3H), 4.06 (t,J=5.2 Hz, 2H), 3.23 (t, J=5.2 Hz, 2H), 2.73 (s, 3H), 2.64 (s, 3H);LC-MS: method A, RT=2.360 min, MS (ESI) m/z: 539.2 (M+H)⁺. AnalyticalHPLC purity (method B): 100%.

Example 27N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Intermediate 27A: tert-butyl (2-(3-chloro-4-nitrophenoxy)ethyl)carbamate

To a solution of tert-butyl (2-hydroxyethyl)carbamate (918 mg, 5.70mmol) in THF (8 mL) was added 0.5 M potassium bis(trimethylsilyl)amidein toluene (12.53 mL, 6.27 mmol). The reaction mixture was stirred atroom temperature for 20 min. 2-Chloro-4-fluoro-1-nitrobenzene (500 mg,2.85 mmol) was added and the reaction mixture was stirred at roomtemperature for 0.5 h, then at 55° C. for 1.5 h. The mixture was dilutedwith EtOAc, quenched with saturated ammonium chloride. The organic layerwas washed with saturated sodium bicarbonate, brine, dried over sodiumsulfate and concentrated. The crude product was purified by flashchromatography (loading in chloroform, 0% to 45% EtOAc in hexane over 15min using a 40 g silica gel cartridge). The desired fractions werecombined and concentrated to yield Intermediate 27A (425 mg, 1.342 mmol,47.1% yield) as yellow liquid. ¹H NMR (500 MHz, chloroform-d) δ8.04-8.00 (d, J=9.1 Hz, 1H), 7.05 (d, J=2.8 Hz, 1H), 6.90 (dd, 2.5 Hz,1H), 4.14-4.10 (m, 2H), 3.58 (q, J=5.3 Hz, 2H), 1.50 (s, 9H); LC-MS:method A, RT=1.97 min, MS (ESI) m/z: 261.1 and 263.1 (M-t-Bu)⁺.

Intermediate 27B: tert-butyl (2-(4-amino-3-chlorophenoxy)ethyl)carbamate

To a solution of Intermediate 27A (0.42 g, 1.326 mmol) in MeOH (10 mL)was added ammonium chloride (1.135 g, 21.22 mmol) and zinc dust (0.694g, 10.61 mmol). The reaction mixture was stirred at room temperature for30 min. HPLC and LCMS indicated a completion of the reaction. MeOH wasremoved under vacuum. The residue was diluted with EtOAc/saturatedsodium bicarbonate and stirred at room temperature for 10 min. Themixture was filtered to remove insoluble material. The filtrate wascollected, organic layer was washed with brine, dried over sodiumsulfate, concentrated to give Intermediate 27B (380 mg, 1.325 mmol, 100%yield) as oil. ¹H NMR (500 MHz, chloroform-d) δ 6.87 (d, J=2.5 Hz, 1H),6.75-6.68 (m, 2H), 4.98 (br. s., 1H), 3.95 (t, J=5.2 Hz, 2H), 3.51 (t,J=5.0 Hz, 2H), 1.48 (s, 9H); LC-MS: method A, RT=1.47 min, MS (ESI) m/z:187.1 and 189.1 (M-Boc)⁺.

Intermediate 27C:tert-butyl(2-((2-amino-4-chlorobenzo[d]thiazol-6-yl)oxy)ethyl) carbamate

To Intermediate 27B (465 mg, 1.622 mmol) in acetonitrile (5.0 mL) wasadded ammonium thiocyanate (216 mg, 2.84 mmol). The reaction mixture wasstirred at room temperature for 10 min. Benzyltrimethylammoniumtribromide (854 mg, 2.189 mmol) in acetonitrile (2.0 mL) was addeddropwise (5 min). The reaction mixture was stirred at room temperaturefor 30 min. HPLC and LCMS indicated ca 30% starting material present.Then another portion of ammonium thiocyanate (211 mg, 2.77 mmol) andbenzyltrimethylammonium tribromide (415 mg, 1.06 mmol) were added. Thereaction mixture was left stirring at room temperature overnight.Acetonitrile was removed under vacuum. The mixture was diluted withEtOAc, THF/saturated sodium bicarbonate. The insoluble material wasremoved by filtration. The organic layer of the filtrate was collected,washed with brine, dried over sodium sulfate and concentrated to giveIntermediate 27C (460 mg, 1.204 mmol, 74.3% yield) as yellow solid thatwas used for the next step without further purification. ¹H NMR (500MHz, DMSO-d₆) δ 7.59 (s, 2H), 7.30 (d, J=2.5 Hz, 1H), 7.01-6.96 (m, 1H),6.92 (d, J=2.5 Hz, 1H), 3.95 (t, J=5.8 Hz, 2H), 3.27 (q, J=5.5 Hz, 2H),1.39 (s, 9H); LC-MS: method A, RT=1.67 min, MS (ESI) m/z: 344.1 (M+H)⁺.

Intermediate 27D: tert-butyl(2((2-bromo-4-chlorobenzo[d]thiazol-6-yl)oxy)ethyl) carbamate

Tert-butyl nitrite (0.249 mL, 1.885 mmol) was added to copper (II)bromide (421 mg, 1.885 mmol) in acetonitrile (6 mL) under argon. Thereaction mixture was stirred at room temperature for 10 min.Intermediate 27C (405 mg, 1.178 mmol) suspended in acetonitrile (6 mL)was added dropwise. The reaction mixture was stirred at room temperaturefor 20 min. HPLC and LCMS indicated a completion of the reaction. Thereaction mixture was diluted with EtOAc, quenched with 0.5N HCl. Afterstirring at room temperature for 10 min, the organic layer of thefiltrate was collected, washed with 0.5 N HCl, saturated sodiumbicarbonate, brine, dried over sodium sulfate and concentrated. Thecrude product was purified by flash chromatography (loading inchloroform, 0% to 35% EtOAc in hexane over 18 min using a 24 g silicagel cartridge). The desired fractions were combined and concentrated toyield Intermediate 27D (411 mg, 1.008 mmol, 86% yield) as a semi solidwhich was lyophilized to a solid. ¹H NMR (500 MHz, chloroform-d) δ 7.18(d, J=2.2 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 4.98 (br. s., 1H), 4.09 (t,J=5.1 Hz, 2H), 3.58 (q, J=5.0 Hz, 2H), 1.48 (s, 9H); LC-MS: method A,RT=1.72 min, MS (ESI) m/z: 407.0 and 409.0 (M+H)⁺.

Intermediate 27E: tert-butyl(2-((4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate

To Intermediate 27D (358 mg, 0.878 mmol) and Intermediate I-1 (295 mg,0.878 mmol) was added toluene (6 mL) and EtOH (2 mL). The reactionmixture was stirred at room temperature until solids are dissolved then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (35.9 mg, 0.044 mmol) was added. The flaskwas degassed and flushed with argon. Sodium carbonate (2M, 0.878 mL,1.756 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then put in microwave reactor at 120° C.for 35 min. HPLC and TLC indicated a completion of the reaction. To thereaction mixture was added EtOAc/water, stirred at room temperature for10 min. The insoluble material was removed by filtration. The filtratewas extracted with EtOAc, washed with brine and concentrated. The crudeproduct was purified by flash chromatography (loading in chloroform, 0%to 35% EtOAc in hexanes over 15 min using a 24 g silica gel cartridge).The desired fractions were combined and concentrated to yieldIntermediate 27E (421 mg, 0.784 mmol, 89% yield) as yellow solid. ¹H NMR(400 MHz, acetonitrile-d₃) δ 8.77 (d, J=1.5 Hz, 1H), 8.72 (s, 1H), 7.82(dd, J=1.9, 1.0 Hz, 1H), 7.71 (t, J_(HF)=71.53 Hz, 1H), 7.50 (d, J=2.4Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 4.12 (t, J=5.5 Hz, 2H), 3.49 (q, J=5.6Hz, 2H), 2.71 (s, 3H), 1.45 (s, 9H); ¹⁹F NMR (376 MHz, acetonitrile-d₃)δ −90.04 (s, 2F); LC-MS: Method A, 40 to 100% B. RT=2.44 min, MS (ESI)m/z: 537.2 (M+H)⁺.

Intermediate 27F: tert-butyl(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate

To Intermediate 27E (400 mg, 0.745 mmol) in DMF (5.0 mL) was added 0.5 NNaOMe in MeOH (3.28 mL, 1.639 mmol). The reaction mixture was stirred atroom temperature for 40 min, diluted with THF (3.0 mL) and EtOAc (10 mL)and quenched with 1.0 N HCl (1.862 mL, 1.862 mmol). THF (50 mL) wasadded followed with brine. The mixture turned to a clean solution. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated to give Intermediate 27F (370 mg, 0.739 mmol, 99% yield) asyellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.57 (d, J=1.9Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 7.29 (d,J=2.5 Hz, 1H), 4.10 (t, J=5.78 Hz, 2H), 4.09 (s, 3H), 3.38-3.34 (m, 2H),2.65 (s, 3H), 1.40 (s, 9H); LC-MS: Method A, 40 to 100% B. RT=2.44 min,MS (ESI) m/z: 501.2 and 503.2 (M+H)⁺.

Intermediate 27G2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanamine hydrochloride

To Intermediate 27F (0.32 g, 0.639 mmol) was added 4.0 N HCl in dioxane(15.97 mL, 63.9 mmol), followed by MeOH (8.0 mL). The reaction mixturewas stirred at 45° C. for 15 min, and then at room temperature for 30min. HPLC indicated a completion of reaction. Solvent was removed undervacuum. The crude was partitioned between EtOAc/saturated sodiumbicarbonate. The organic layer was washed with brine, dried over sodiumsulfate, concentrated and lyophilized to give Intermediate 27G (50 mg,0.114 mmol, 17.90% yield). ¹H NMR (400 MHz, methanol-d₄) δ 8.19 (d,J=1.8 Hz, 1H), 8.05 (s, 1H), 7.31 (s, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.12(d, J=2.2 Hz, 1H), 4.27 (t, J=5.0 Hz, 2H), 3.94 (s, 3H), 3.44 (t, J=5.0Hz, 2H), 2.44 (s, 3H); LC-MS: method A, RT=1.99 min, MS (ESI) m/z: 401.1and 403.1 (M+H)⁺.

Example 27

To Intermediate 27G (24 mg, 0.055 mmol) in DMF (0.8 mL) was added DIEA(0.058 mL, 0.329 mmol). After stirring at room temperature for 2 min,benzenesulfonyl chloride (10.61 μl, 0.082 mmol) was added and thereaction mixture was stirred at room temperature for 20 min. Thereaction mixture was quenched with MeOH (1.0 mL). The crude material waspurified via preparative LC/MS (method C, 40-85% B over 20 minutes, thena 5-minute hold at 100% B). Fractions containing the desired productwere combined and dried via centrifugal evaporation to yield Example 27(6.4 mg, 22% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.57 (d,J=1.7 Hz, 1H), 7.87-7.85 (m, 1H), 7.85-7.83 (m, 2H), 7.64-7.58 (m, 4H),7.15 (d, J=2.2 Hz, 1H), 4.11-4.07 (m, 5H), 3.22 (br. s., 2H), 2.65 (s,3H); LC-MS: method A, RT=2.55 min, MS (ESI) m/z: 541.0 (M+H)⁺.Analytical HPLC purity (method B): 100%.

Example 28N-(2-((4-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

To Intermediate 27G (30 mg, 0.069 mmol) in DMF (0.8 mL) was added DIEA(0.060 mL, 0.343 mmol). After stirring at room temperature for 4 min,4-fluorobenzenesulfonyl chloride (14.68 mg, 0.075 mmol) was added andthe reaction mixture was stirred at room temperature for 30 min. Thereaction was quenched with MeOH (1.0 mL) and purified via preparativeLC/MS (method C, 45-85% B over 20 minutes, then a 5-minute hold at 100%B). Fractions containing the desired product were combined and dried viacentrifugal evaporation to yield Example 28 (8.9 mg, 22% yield). ¹H NMR(500 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.57 (d, J=1.7 Hz, 1H), 7.97-7.89 (m,3H), 7.84 (s, 1H), 7.64 (d, J=2.2 Hz, 1H), 7.45-7.40 (m, 2H), 7.14 (d,J=2.2 Hz, 1H), 4.11-4.07 (m, 5H), 3.24 (t, J=5.2 Hz, 2H), 2.65 (s, 3H);LC-MS: method A, RT=2.50 min, MS (ESI) m/z: 559.0 and 561.0 (M+H)⁺.Analytical HPLC purity (method B): 100%.

Example 294-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

To Intermediate I-2 (41 mg, 0.177 mmol), Intermediate I-5 (79 mg, 0.177mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex with dichloromethane (1:1) (7.21 mg, 8.83 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.177mL, 0.353 mmol). The reaction mixture was heated in a microwave reactorat 130° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. To the reaction mixture was added EtOAc/water. The organiclayer was collected, dried over sodium sulfate, concentrated. The cruderesidue was dissolved in DMSO/MeOH (3.5 mL each), purified using apreparative HPLC (method A, 65-100% B in 10 min; then 100% B in 2 min,RT=7.2 min). The desired fractions were placed in a SpeedVac overnightto remove solvent, then lyophilized to give Example 29 (59 mg, 0.106mmol, 59.8% yield). ¹H NMR (400 MHz, acetonitrile-d₃) δ 9.05 (s, 1H),8.88 (s, 1H), 7.98-7.89 (m, 3H), 7.26 (td, J=8.7, 1.8 Hz, 3H), 6.85 (s,1H), 5.95 (br. s., 1H), 4.82 (s, 2H), 4.07 (t, J=4.6 Hz, 2H), 3.56 (s,3H), 3.39-3.31 (m, 2H), 2.80 (s, 3H), 2.72 (s, 3H); ¹⁹F NMR (471 MHz,acetonitrile-d₃) δ −107.47 (s, 1F); LC-MS: method A, RT=2.32 min, MS(ESI) m/z: 553.1 (M+H)⁺. Analytical HPLC (method A): Sunfire, RT=10.81min, 99% purity; XBridge, RT=6.64 min, 99% purity.

Example 30N-(2-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Intermediate 30AN-(2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

To Intermediate I-1 (40 mg, 0.119 mmol), Intermediate I-5 (48.2 mg,0.108 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (7.07 mg, 8.65 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.119mL, 0.238 mmol). The reaction mixture was heated in a microwave reactorat 130° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. To the reaction mixture was added EtOAc/water. The organiclayer was collected, dried over sodium sulfate, concentrated. The crudeproduct was purified by flash chromatography (loading in chloroform, 0%to 75% EtOAc in hexane over 20 min using a 12 g silica gel cartridge).The desired fractions were combined and concentrated to yieldIntermediate 30A (50 mg, 0.087 mmol, 80% yield) as yellow solid. LC-MS:method A, RT=2.71 min, MS (ESI) m/z: 575.1 (M+H)⁺.

Example 30

To Intermediate 30A (14 mg, 0.024 mmol) dissolved in EtOH (0.5 mL) andTHF (0.4 mL) was added sodium ethoxide in ethanol (0.027 mL, 0.073 mmol)(21% by weight). The reaction mixture was stirred at room temperaturefor 15 min., another portion of sodium ethoxide in ethanol (0.027 mL,0.073 mmol) was added. The mixture was left stirring at room temperatureovernight. LCMS indicated a completion of the reaction. Solvent wasremoved and the residue was dissolved in DMSO/MEOH (1:1) and purifiedvia preparative LC/MS (method D, 65-100% B over 10 minutes, then a5-minute hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to yield Example 30 (11.3mg). ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.58 (d, J=1.1 Hz, 1H),7.91 (dd, J=8.5, 5.5 Hz, 2H), 7.78 (s, 1H), 7.46-7.41 (m, 3H), 6.86 (s,1H), 4.54 (q, J=7.1 Hz, 2H), 4.05 (t, J=5.2 Hz, 2H), 3.23 (t, J=5.2 Hz,2H), 2.73 (s, 3H), 2.64 (s, 3H), 1.45 (t, J=7.2 Hz, 3H); LC-MS: methodA, RT=2.48 min, MS (ESI) m/z: 553.3 (M+H)⁺. Analytical HPLC purity(method B): 100%.

Example 31N-(2-((2-(2-ethyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Intermediate 31A: tert-butyl(2-bromo-4-methyl-6-nitrophenyl)(2-oxobutyl)carbamate

To Intermediate I-1B (1.28 g, 3.87 mmol) in DMF (15 mL) at roomtemperature was added Cs₂CO₃ (2.204 g, 6.76 mmol). The brown solutionwas stirred at room temperature for 5 min, followed by addition of1-bromobutan-2-one (0.592 mL, 5.80 mmol) in acetonitrile (0.4 mL). Thebrown solution turned yellow. The reaction mixture was stirred at roomtemperature for 15 min. TLC indicated a completion of the reaction Themixture was diluted with EtOAc, washed with water, brine, dried oversodium sulfate and concentrated. The crude product was purified by flashchromatography (loading in chloroform, 0% to 40% EtOAc in hexane over 10min using a 40 g silica gel cartridge). The desired fractions werecombined and concentrated to yield Intermediate 31A (1.5 g, 3.74 mmol,97% yield) as yellow liquid. ¹H NMR (400 MHz, chloroform-d) indicatedpresence of two rotamers. δ 7.73-7.67 (m, 2H), 4.51-4.05 (m, 2H),2.57-2.49 (m, 2H), 2.47 and 2.42 (s, 3H), 1.53 and 1.37 (s, 9H), 1.18and 1.13 (t, J=7.26 Hz, 3H); LC-MS: method A, RT=1.99 min, MS (ESI) m/z:310.0 and 303.0 (M-Boc)⁺.

Intermediate 31B: 5-bromo-2-ethyl-7-methylquinoxaline

To Intermediate 31A (1.55 g, 3.86 mmol) in ethyl acetate (8 mL) wasadded 4.0 N HCl in dioxane (11.59 mL, 46.4 mmol) and the reactionmixture was stirred at room temperature for 45 min. HPLC indicated acompletion of the reaction. Solvent was removed under vacuum to give thedeprotected intermediate as yellow oil. The deprotected intermediate wasdissolved in THF (20 mL). Tin (II) chloride dihydrate (2.88 g, 12.75mmol) was added, followed by concentrated HCl (0.476 mL, 5.79 mmol). Themixture was placed and stirred in oil bath pre-heated at 45° C. for 1.0h. HPLC and LCMS indicated a completion of the reaction. The reactionmixture was diluted with EtOAc/water and neutralized with saturatedsodium bicarbonate. The reaction mixture was stirred at room temperaturefor 15 min, the precipitate was removed by a separatory funnel. Theorganic layer was washed with saturated sodium bicarbonate, brine, driedover sodium sulfate and concentrated to give Intermediate 31B (0.93 g,3.70 mmol, 96% yield) as a light yellow solid. ¹H NMR (400 MHz,chloroform-d) δ 8.70 (s, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.72 (dd, J=1.8,0.9 Hz, 1H), 2.99 (q, J=7.7 Hz, 2H), 2.50 (s, 3H), 1.36 (t, J=7.6 Hz,3H); LC-MS: method A, RT=1.93 min, MS (ESI) m/z: 251.1 and 253.1 (M+H)⁺.

Intermediate 31C: (2-ethyl-7-methylquinoxalin-5-yl)boronic acid

A mixture of Intermediate 31B (129 mg, 0.514 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (261 mg,1.027 mmol), potassium acetate (101 mg, 1.027 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (16.78 mg, 0.021 mmol) in dioxane (3.0 mL)was degassed by bubbling argon for 10 min. The reaction vial was sealedand heated in microwave reactor at 130° C. for 30 min. LCMS indicatedcomplete conversion of starting material. The mixture was diluted withEtOAc/water, insoluble material was removed by filtration. The filtratewas extracted with EtOAc, washed with brine and dried over sodiumsulfate.

The crude residue was dissolved in MeOH/DMSO (1:1) and purified using apreparative HPLC (method A, 20-100% B in 10 min; then 100% B in 2 min;RT=3.5 min). The desired fractions were placed in a SpeedVac overnightto remove solvent, then lyophilized to give Intermediate 31C (50 mg,0.231 mmol, 45.1% yield) as a solid. ¹H NMR in CDCl₃ suggested presenceof isomeric forms. HPLC and LCMS indicated a single peak. LC-MS: methodA, RT=1.86 min, MS (ESI) m/z: 217.0 (M+H)⁺.

Example 31

To Intermediate 31C (8.73 mg, 0.040 mmol), Intermediate I-5 (18 mg,0.040 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.64 mg, 3.23 μmol) was addedtoluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.040mL, 0.081 mmol). The reaction mixture was heated in a microwave reactorat 120° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. To the reaction mixture was added EtOAc/water. The organiclayer was collected, dried over sodium sulfate, concentrated. The crudeproduct was purified via preparative LC/MS (method D, 60-100% B over 10minutes, then a 5-minute hold at 100% B). Fractions containing thedesired product were combined and dried via centrifugal evaporation toyield Example 31 (15.2 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (s, 1H),8.75 (s, 1H), 8.04 (br. s., 1H), 7.99 (s, 1H), 7.91 (dd, J=8.7, 5.4 Hz,2H), 7.47-7.41 (m, 3H), 6.87 (s, 1H), 4.06 (t, J=5.1 Hz, 2H), 3.23 (t,J=5.1 Hz, 2H), 3.09 (q, J=7.7 Hz, 2H), 2.74 (s, 3H), 2.68 (s, 3H), 1.40(t, J=7.6 Hz, 3H); LC-MS: method A, RT=2.59 min, MS (ESI) m/z: 537.3(M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 32 methyl5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate

Intermediate 32A: (2-(methoxycarbonyl)-7-methylquinoxalin-5-yl)boronicacid

A mixture of methyl 5-bromo-7-methylquinoxaline-2-carboxylate (103 mg,0.366 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(205 mg, 0.806 mmol), potassium acetate (90 mg, 0.916 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (11.97 mg, 0.015 mmol) in dioxane (3.0 mL)was degassed by bubbling argon for 10 min. The reaction vial was sealedand heated in microwave reactor at 130° C. for 30 min. LCMS indicatedcomplete conversion of starting material. The mixture was diluted withEtOAc/water, insoluble material was removed by filtration. The filtratewas extracted with EtOAc, washed with brine and dried over sodiumsulfate. The crude residue was dissolved in MeOH/DMSO (1:1) and purifiedusing a preparative HPLC (method A, 30-100% B in 10 min; then 100% B in2 min; RT=3.5 min). The desired fractions were placed in a SpeedVacovernight to remove solvent, then lyophilized to give Intermediate 32A(46 mg, 0.187 mmol, 51.0% yield) as a white solid. ¹H NMR (400 MHz,methanol-d₄) δ 9.43 (s, 1H), 8.30 (br. s., 1H), 8.07 (br. s., 1H), 4.11(s, 3H), 2.64 (s, 3H); LC-MS: method A, RT=1.64 min, MS (ESI) m/z: 247.1boronic acid (M+H)⁺.

Intermediate 32B5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylicacid

To Intermediate 32A (24 mg, 0.098 mmol), Intermediate I-5 (43.4 mg,0.098 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (3.98 mg, 4.88 μmol) was addedtoluene (1.5 mL) and MeOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.098mL, 0.195 mmol). The reaction mixture was heated in a microwave reactorat 120° C. for 30 min. LCMS indicated a completion of the reaction tothe acid. The mixture was diluted with EtOAc/THF (40 Ml/20 mL),acidified with 0.5 N HCl. The organic layer was washed with brine, driedover sodium sulfate and concentrated, purified via preparative LC/MS(method D, 15-55% B over 20 minutes, then a 5-minute hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to yield Intermediate 32B (38.5 mg). ¹H NMR (500MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.91 (s, 1H), 8.16 (br. s., 1H), 8.05 (t,J=5.2 Hz, 1H), 7.98-7.89 (m, 3H), 7.48-7.41 (m, 2H), 6.87 (d, J=1.1 Hz,1H), 4.07 (t, J=5.2 Hz, 2H), 3.25-3.21 (m, 2H), 2.74 (s, 3H), 2.73 (s,3H); LC-MS: method A, RT=2.04 min, MS (ESI) m/z: 553.2 (M+H)⁺.

Example 32

To a suspension of Intermediate 32B (28 mg, 0.051 mmol) in CH₂Cl₂ (2.0mL) and MeOH (0.5 mL) at room temperature was added(diazomethyl)trimethylsilane 2.0 M in diethyl ether (0.076 mL, 0.152mmol). The suspension turned clear. The reaction mixture was stirred atroom temperature for 1.0 h. HPLC and LCMS indicated a completion of thereaction. Solvent was removed under vacuum. The crude was purified viapreparative LC/MS (method D, 50-90% B over 10 minutes, then a 5-minutehold at 100% B). Fractions containing the desired product were combinedand dried via centrifugal evaporation to yield Example 32 (16.4 mg). ¹HNMR (500 MHz, DMSO-d₆) δ 9.50 (s, 1H), 8.92 (d, J=1.1 Hz, 1H), 8.18 (s,1H), 7.92 (dd, J=8.5, 5.2 Hz, 2H), 7.48-7.45 (m, 2H), 7.45-7.42 (m, 2H),6.87 (s, 1H), 4.07 (t, J=5.4 Hz, 2H), 4.04 (s, 3H), 3.24 (br. s., 2H),2.74 (s, 3H), 2.73 (s, 3H); LC-MS: method A, RT=2.28 min, MS (ESI) m/z:567.2 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 33N-(2-((2-(2-cyclopropoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Intermediate 33A: cyclopropanol

To a solution of cyclopropylboronic acid (0.65 g, 7.57 mmol) in 10% NaOH(5.0 mL) at 0° C. was added a solution of 30% hydrogen peroxide (21.44mL, 189 mmol) dropwise. The reaction mixture was stirred at 0° C. for1.5 h. The reaction mixture was diluted with diethyl ether, quenchedwith saturated NaHSO₃ (15 mL) at 0° C. After stirring for 15 min, theorganic layer was collected, washed with brine, dried over sodiumsulfate and concentrated at 0° C. to give Intermediate 33A (0.16 g, 2.75mmol, 36.4% yield) as colorless liquid. It was used for the next stepwithout further purification. ¹H NMR (400 MHz, chloroform-d) δ 3.62-3.41(m, 1H), 0.69-0.40 (m, 4H).

Example 33

To 60% sodium hydride (15.66 mg, 0.392 mmol) was added Intermediate 33A(37.9 mg, 0.653 mmol) in DMF (0.5 mL). The reaction mixture was stirredat room temperature for 15 min. A solution of Intermediate 30A (15 mg,0.026 mmol) in DMF (1.0 mL) was added. The reaction mixture was stirredat room temperature for 25 min. LCMS indicated a completion of thereaction. The reaction mixture was diluted with EtOAc, quenched with 0.5N HCl. The organic layer was collected, washed with brine, dried oversodium sulfate and concentrated. The crude was dissolved inDMF/acetonitrile (1:1, 2.2 mL) and purified via preparative LC/MS(method D, 60-100% B over 10 minutes, then a 5-minute hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to yield Example 33 (8.6 mg). ¹H NMR (500 MHz,DMSO-d₆) δ 8.67 (s, 1H), 8.59 (s, 1H), 7.90 (dd, J=8.5, 5.2 Hz, 2H),7.83 (s, 1H), 7.45-7.40 (m, 3H), 6.85 (s, 1H), 4.53-4.49 (m, 1H), 4.05(t, J=5.4 Hz, 2H), 3.22 (t, J=5.2 Hz, 2H), 2.73 (s, 3H), 2.64 (s, 3H),0.93-0.88 (m, 2H), 0.87-0.82 (m, 2H); LC-MS: method A, RT=2.67 min, MS(ESI) m/z: 565.1 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 344-fluoro-N-(2-((2-(2-(fluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Intermediate 34A: methyl 2-((5-bromo-7-methylquinoxalin-2-yl)oxy)acetate

To sodium hydride, 60% (411 mg, 10.27 mmol) in DMF (15 mL) cooled with awater bath was added methyl 2-hydroxyacetate (0.959 mL, 12.45 mmol). Thereaction mixture was stirred for 20 min. A solution of Intermediate I-1G(900 mg, 3.11 mmol) in DMF (5 mL) was added at room temperature. Thereaction mixture was stirred at room temperature for 0.5 h. HPLCindicated a completion of the reaction. The reaction mixture was dilutedwith EtOAc, quenched with 0.5 N HCl. The organic layer was washed withbrine, dried over sodium sulfate and concentrated. The crude product waspurified by flash chromatography (loading in chloroform, 0% to 30% EtOAcin hexane over 12 min using a 40 g silica gel cartridge). The desiredfractions were combined and concentrated to yield Intermediate 34A (811mg, 2.61 mmol, 84% yield) as a white solid. ¹H NMR (400 MHz,chloroform-d) δ 8.51 (s, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.44 (dd, 0.9 Hz,1H), 4.97 (s, 2H), 3.71 (s, 3H), 2.41 (s, 3H); LC-MS: method A, RT=1.97min, MS (ESI) m/z: 311.0 and 313.0 (M+H)⁺.

Intermediate 34B: 2-((5-bromo-7-methylquinoxalin-2-yl)oxy)acetic acid

To Intermediate 34A (811 mg, 2.61 mmol) dissolved in THF (16 mL) at roomtemperature was added 1.0 N NaOH (4.56 mL, 4.56 mmol). The reactionmixture was stirred at room temperature for 15 min. HPLC and LCMSindicated a completion of the reaction. The mixture was diluted withEtOAc/water, quenched with 1.0 N HCl (4.95 mL, 4.95 mmol). The organiclayer was collected, washed with brine, dried over sodium sulfate andconcentrated to give Intermediate 34B (730 mg, 2.457 mmol, 94% yield) asa white solid. ¹H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 7.77 (d,J=1.5 Hz, 1H), 7.58 (dd, J=1.5, 0.9 Hz, 1H), 5.12 (s, 2H), 2.53 (s, 3H);LC-MS: method A, RT=1.81 min, MS (ESI) m/z: 297.0 and 299.0 (M+H)⁺.

Intermediate 34C: 5-bromo-2-(fluoromethoxy)-7-methylquinoxaline

To a suspension of Intermediate 34B (400 mg, 1.346 mmol) indichloromethane (30 mL) at room temperature was added xenon difluoride(251 mg, 1.481 mmol). The reaction mixture was stirred at roomtemperature for 4.0 h, followed by addition of another portion of xenondifluoride (251 mg, 1.481 mmol). The reaction mixture was left stirringat room temperature overnight. The suspension turned to a clear solutionat this point. A third portion of xenon difluoride (387 mg, 2.289 mmol)was added and the reaction mixture was stirred at room temperature for4.0 h. The reaction was quenched by addition of saturated sodiumbicarbonate, extracted with dichloromethane, dried over sodium sulfateand concentrated. The crude product was purified by flash chromatography(loading in chloroform, 0% to 30% EtOAc in hexane over 15 min using a 24g silica gel cartridge). The desired fractions were combined andconcentrated to yield Intermediate 34C (55 mg, 0.203 mmol, 15.07% yield)as a white solid. ¹H NMR (400 MHz, chloroform-d) δ 8.60 (s, 1H), 7.82(d, J=1.5 Hz, 1H), 7.68 (dd, J=1.7, 1.0 Hz, 1H), 6.28 and 6.16 (d,J_(HF)=51.28 Hz, 2H), 2.56 (s, 3H); ¹⁹F NMR (376 MHz, chloroform-d) δ−157.89 (s, 1F); LC-MS: method A, RT=1.97 min, MS (ESI) m/z: 271.0 and273.0 (M+H)⁺.

Intermediate 34D: (2-(fluoromethoxy)-7-methylquinoxalin-5-yl)boronicacid

A mixture of Intermediate 34C (48 mg, 0.177 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (71.9 mg,0.283 mmol), potassium acetate (34.8 mg, 0.354 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (5.78 mg, 7.08 μmol) in dioxane (2.0 mL) wasdegassed by bubbling argon for 5 min. The reaction mixture was heated ina microwave reactor at 120° C. for 30 min. HPLC and LCMS indicatedcomplete conversion of starting material. The mixture was diluted withEtOAc, washed with brine. The organic layer was dried over sodiumsulfate. The crude residue was purified using a preparative HPLC (methodA, 30-100% B in 10 min; then 100% B in 2 min). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto give Intermediate 34D (20 mg, 0.085 mmol, 47.9% yield) as a whitesolid. ¹H NMR (400 MHz, methanol-d₄) δ 8.48 (s, 1H), 8.02 (br. s., 1H),7.75 (br. s., 1H), 6.24 and 6.14 (d, J_(HF)=51.50 Hz, 1H), 2.56 (s, 3H);NMR (376 MHz, methanol-d₄) δ −158.05 (br. s., 1F); LC-MS: method A,RT=1.87 min, MS (ESI) m/z: 237.0 (M+H)⁺.

Example 34

To Intermediate 34D (9.54 mg, 0.040 mmol), Intermediate I-5 (18 mg,0.040 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.64 mg, 3.23 μmol) was addedtoluene (0.9 mL) and EtOH (0.3 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.040mL, 0.081 mmol). The reaction mixture was heated in a microwave reactorat 130° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. To the reaction mixture was added EtOAc/water. The organiclayer was collected, dried over sodium sulfate, concentrated. The crudeproduct was purified via preparative LC/MS (method G, 60-100% B over 20minutes, then a 5-minute hold at 100% B). Fractions containing thedesired product were combined and dried via centrifugal evaporation toyield Example 34 (19.9 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 8.88 (s, 1H),8.68 (s, 1H), 7.98-7.87 (m, 3H), 7.48-7.41 (m, 3H), 6.87 (s, 1H), 6.37and 6.23 (d, J_(HF)=51.44 Hz, 2H), 4.06 (t, J=5.1 Hz, 2H), 3.24 (t,J=5.1 Hz, 2H), 2.74 (s, 3H), 2.67 (s, 3H); LC-MS: method A, RT=2.52 min,MS (ESI) m/z: 557.1 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 352-(2-methoxy-7-methylquinoxalin-5-yl)-4-methyl-6-((2-phenyl-1H-imidazol-5-yl)methoxy)benzo[d]thiazole

Intermediate 35A: 5-(chloromethyl)-2-phenyl-1H-imidazole hydrochloride

To (2-phenyl-1H-imidazol-5-yl)methanol (0.216 g, 1.240 mmol) at roomtemperature was added thionyl chloride (0.453 ml, 6.20 mmol). Thereaction mixture was stirred at room temperature for 10 min, and then at65° C. for 2.0 h. The reaction mixture was diluted with chloroform (5.0mL) and the resulting solution was evaporated. Additional co-evaporationwith chloroform gave Intermediate 35A (0.28 g, 1.222 mmol, 99% yield) asa brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21-8.15 (m, 2H), 7.83 (s,1H), 7.67-7.62 (m, 3H), 4.93 (s, 2H).

Intermediate 35B:2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol

To Intermediate 26D (561 mg, 1.150 mmol) dissolved in THF (4.0 mL) atroom temperature was added 5.4 M sodium methoxide in MeOH (0.746 mL,4.03 mmol). The reaction mixture turned deep red. The reaction mixturewas stirred at room temperature for 20 min. HPLC and LCMS indicated acompletion of the reaction. The reaction mixture was diluted with EtOAc,quenched with 1.0 N HCl (2.88 mL, 2.88 mmol). The organic layer waswashed with brine, dried and concentrated to give Intermediate 35B (300mg, 0.889 mmol, 77% yield) as yellow solid. ¹H NMR (400 MHz,chloroform-d) δ 8.47 (d, J=1.5 Hz, 1H), 8.43 (s, 1H), 7.63 (s, 1H), 7.09(d, J=2.2 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 3.73 (s, 3H), 2.69 (s, 3H),2.55 (s, 3H); LC-MS: Method A, 50 to 100% B. RT=2.45 min, MS (ESI) m/z:338.1 (M+H)⁺.

Example 35

To a stirred solution of Intermediate 35B (25 mg, 0.074 mmol) and cesiumcarbonate (97 mg, 0.296 mmol) in DMF (0.8 mL) at room temperature wasadded a solution of Intermediate 35A (37.3 mg, 0.163 mmol) in DMF (0.8mL) dropwise. The reaction mixture was stirred at room temperature for0.5 h, then another portion of Intermediate 35A (37.3 mg, 0.163 mmol) inDMF (0.8 mL) was added. The reaction mixture was stirred at roomtemperature for 1.0 h, diluted with EtOAc, quenched with ammoniumchloride. The organic layer was collected, washed with brine, dried oversodium sulfate and concentrated. The crude material was purified viapreparative LC/MS (method D, 50-90% B over 20 minutes, then a 5-minutehold at 100% B). Fractions containing the desired product were combinedand dried via centrifugal evaporation to yield Example 35 (6.1 mg). ¹HNMR (500 MHz, DMSO-d₆) δ 8.75 (br. s., 1H), 8.61 (br. s., 1H), 8.02 (d,J=6.9 Hz, 2H), 7.84 (br. s., 2H), 7.74 (br. s., 1H), 7.61 (d, J=7.4 Hz,3H), 7.12 (br. s., 1H), 5.26 (br. s., 2H), 4.09 (br. s., 3H), 2.77 (br.s., 3H), 2.66 (br. s., 3H); LC-MS: method A, RT=2.54 min, MS (ESI) m/z:494.2 (M+H)⁺. Analytical HPLC purity (method B): 98%.

Example 36N-benzyl-2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetamide

Intermediate 36A: methyl2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetate

To a suspension of Intermediate 35B (240 mg, 0.711 mmol) in DMF (10 mL)was added THF (2.0 mL) and cesium carbonate (695 mg, 2.134 mmol). Thesolution turned from yellow to brown. Methyl bromoacetate (0.328 mL,3.56 mmol) was added dropwise. The reaction mixture was stirred at roomtemperature for 20 min, then at 50° C. for 2.0 h. HPLC and LCMSindicated a completion of the reaction. The reaction mixture was dilutedwith EtOAc/THF and water. The product could not dissolve at this stage.The organic suspension was separated from aqueous solution, concentratedto remove solvent and water. The crude was triturated with a mixture ofacetonitrile and water. The solid was collected by filtration, washedwith acetonitrile and dried to give Intermediate 36A (280 mg, 0.684mmol, 96% yield) as yellow solid. ¹H NMR was not taken due to very poorsolubility in DMSO-d₆. LC-MS: method A, RT=1.17 min, MS (ESI) m/z: 410.0(M+H)⁺.

Intermediate 36B2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)aceticacid

To a suspension of Intermediate 36A (44 mg, 0.107 mmol) in THF (2.0 mL)and MeOH (0.5 mL) at room temperature was added 1.0 N NaOH (0.537 mL,0.537 mmol). The suspension was stirred at room temperature for 2.0 hwith occasional sonicating (3×) for 1 min. HPLC and LCMS indicated acomplete of reaction. To the reaction mixture was added 1.0 N HCl (0.537mL, 0.537 mmol), followed by addition of EtOAc/water. The organic layerwas washed with brine and dried over sodium sulfate and concentrated.The crude was lyophilized to give Intermediate 36B (42 mg, 0.102 mmol,95% yield) as a light yellow lyophilate. ¹H NMR (500 MHz, methanol-d₄) δ8.57 (d, J=1.9 Hz, 1H), 8.52 (s, 1H), 7.73 (dd, J=1.9, 0.8 Hz, 1H), 7.25(d, J=2.5 Hz, 1H), 6.98 (dd, J=2.5, 0.8 Hz, 1H), 4.68 (s, 2H), 4.11 (s,3H), 2.80 (s, 3H), 2.64 (s, 3H); LC-MS: method A, RT=1.06 min, MS (ESI)m/z: 396.0 (M+H)⁺. Analytical HPLC purity (method B): 96%.

Example 36

To a suspension of Intermediate 36B (12.5 mg, 0.032 mmol) andphenylmethanamine (0.014 mL, 0.126 mmol) in DMF (1.0 mL) was added DIEA(0.044 mL, 0.253 mmol), followed by T₃P 50% wt in EtOAc (0.075 mL, 0.126mmol). The reaction mixture was stirred at room temperature for 1.0 h.HPLC and LCMS indicated a completion of the reaction. The reaction wasquenched by addition of 0.1% TFA in MeOH/water. The crude material waspurified via preparative LC/MS (method D, 60-100% B over 15 minutes,then a 10-minute hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to yieldExample 36 (9.8 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.72 (t,J=6.2 Hz, 1H), 8.62 (d, J=1.7 Hz, 1H), 7.84 (d, J=0.8 Hz, 1H), 7.55 (d,J=2.2 Hz, 1H), 7.33-7.22 (m, 5H), 7.11 (d, J=1.7 Hz, 1H), 4.67 (s, 2H),4.39 (d, J=6.1 Hz, 2H), 4.10 (s, 3H), 2.77 (s, 3H), 2.66 (s, 3H); LC-MS:method A, RT=2.55 min, MS (ESI) m/z: 485.2 (M+H)⁺. Analytical HPLCpurity (method B): 95%.

Example 37 5-(7-chlorobenzofuran-2-yl)-2-methoxy-7-methylquinoxaline

Intermediate 37A: 7-chloro-2-iodobenzofuran

To diisopropylamine (0.280 mL, 1.966 mmol) in THF (4.0 mL) at −78° C.was added 1.6 N n-BuLi in hexanes (1.229 mL, 1.966 mmol). The reactionmixture was stirred at −78° C. for 0.5 h. 7-Chlorobenzofuran (200 mg,1.311 mmol) in THF (1.0 mL) was added, The reaction mixture was stirredat −78° C. for 0.5 h. Iodine (665 mg, 2.62 mmol) in THF (1.0 mL) wasadded dropwise until the brown color persisted (ca 1.3 eq.) The reactionmixture was stirred at −78° C. for 0.5 h, then at room temperature for0.5 h. The reaction mixture was diluted with EtOAc, quenched withsaturated ammonium chloride (5.0 mL) and 10% Na₂S₂O₃ (5.0 mL). Afterstirring at room temperature for 10 min, the organic layer was washedwith brine, dried over sodium sulfate. After evaporation of solvent, thecrude product Intermediate 37A (360 mg, 1.189 mmol, 91% yield) wasobtained as a slightly brown oil. It was used for the next step withoutfurther purification. ¹H NMR (400 MHz, chloroform-d) δ 7.40 (dd, J=7.7,1.3 Hz, 1H), 7.24-7.20 (m, 1H), 7.17-7.11 (m, 1H), 6.99 (s, 1H). LC-MS:method H, 2 to 98% B. RT=1.07 min, MS (ESI) m/z: MW not observed (M+H)⁺.

Intermediate 37B:5-(7-chlorobenzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline

To Intermediate I-1 (45.6 mg, 0.180 mmol), Intermediate 37A (50.0 mg,0.180 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.87 mg, 7.18 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 0.157mL, 0.314 mmol). The reaction mixture was heated in a microwave reactorat 120° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. The crude reaction mixture was diluted with EtOAc/water. Theinsoluble material was removed by filtration. The organic layer waswashed with brine, dried over sodium sulfate and concentrated to giveIntermediate 37B (64 mg, 0.177 mmol, 99% yield) as a brown solid. ¹H NMR(500 MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.24 (d, J=1.9 Hz, 1H), 8.20 (s, 1H),7.90 (t, J_(HF)=71.53 Hz, 1H), 7.83-7.81 (m, 1H), 7.79 (dd, J=7.8, 1.0Hz, 1H), 7.51 (dd, J=7.8, 1.0 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 2.67 (s,3H); LC-MS: method H, RT=2.70 min, MS (ESI) m/z: 361.0 (M+H)⁺.

Example 37

To Intermediate 37B (35 mg, 0.097 mmol) dissolved in THF (1.5 mL) andMeOH (1.5 mL) at room temperature was added 4.3 M sodium methoxide inMeOH (0.090 mL, 0.388 mmol). The reaction mixture was stirred at roomtemperature for 1.0 h. LCMS indicated ca 60% conversion. Then anotherportion of 4.3 M sodium methoxide in MeOH (0.090 mL, 0.388 mmol) wasadded and the reaction was continued at room temperature for 2.0 h. LCMSindicated a completion of the reaction. Methanol was removed undervacuum. The reaction mixture was diluted with EtOAc, quenched with 0.5 NHCl (2.0 mL). The organic layer was washed with saturated sodiumbicarbonate, brine, dried and concentrated. The crude material waspurified via preparative LC/MS (method D, 65-100% B over 20 minutes,then a 8-minute hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to yieldExample 37 (16.0 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.17 (s,1H), 8.10 (d, J=1.7 Hz, 1H), 7.77 (dd, J=7.8, 1.0 Hz, 1H), 7.74 (d,J=0.8 Hz, 1H), 7.49 (dd, J=7.8, 1.0 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H),4.09 (s, 3H), 2.64 (s, 3H); LC-MS: method H. RT=2.76 min, MS (ESI) m/z:325.1 and 327.1 (M+H)⁺. Analytical HPLC purity (method B): 95%.

Example 382-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl(2-methylpyridin-4-yl)carbamate

Intermediate 38A: 2-chloro-1-(2,2-diethoxyethoxy)-4-methoxybenzene

To a suspension of sodium hydride (60%) (0.189 g, 4.73 mmol) in DMF (5.0mL) was added 2-chloro-4-methoxyphenol (0.5 g, 3.15 mmol) dissolved inDMF (3.0 mL) at room temperature. After hydrogen evolution was ceased(20 min at 40° C. oil bath), 2-bromo-1,1-diethoxyethane (0.593 mL, 3.94mmol) was added. The reaction mixture was heated at 160° C. for 18 h.After cooled to room temperature, the reaction mixture was diluted withEtOAc/water. The organic layer was washed with saturated sodiumbicarbonate, brine, dried over sodium sulfate and concentrated to giveIntermediate 38A (0.95 g, 3.46 mmol, 110% yield) as a light yellow oil.It was used for the next step without further purification. ¹H NMR (400MHz, chloroform-d) δ 6.93 (d, J=3.1 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H),6.73 (dd, J=8.9, 3.0 Hz, 1H), 4.84 (t, J=5.2 Hz, 1H), 4.00 (d, J=5.3 Hz,2H), 3.83-3.76 (m, 2H), 3.75 (s, 3H), 3.71-3.64 (m, 2H), 1.27-1.22 (t,J=7.04 Hz, 6H). LC-MS: method H, 2 to 98% B. RT=1.02 min, MS (ESI) m/z:297.0 (M+Na)⁺.

Intermediate 38B: 7-chloro-5-methoxybenzofuran

A mixture of Amberlyst-15 (1.2 g, 2.91 mmol) in chlorobenzene (100 mL)was heated at reflux (oil bath temperature 165° C.) to remove water byazeotropic distillation. Distillate was removed until the volumeremaining in the flask was about 80 mL. To this mixture was then addeddropwise over 1.0 h a solution of Intermediate 38A (0.8 g, 2.91 mmol) inchlorobenzene (9.0 mL). The reaction mixture was stirred at reflux withconstant water removal for another 2.0 h. After cooled to roomtemperature, the Amberlyst-15 was removed by filtration. The filtratedwas concentrated under vacuum, and loaded directly to ISCO column forpurification. The crude product was purified by flash chromatography(loading in chloroform, 0% to 30% EtOAc in hexane over 15 min using a 24g silica gel cartridge). The desired fractions were combined andconcentrated to yield Intermediate 38B (0.32 g, 1.752 mmol, 60.2% yield)as a light yellow oil. ¹H NMR (400 MHz, chloroform-d) δ 7.64 (d, J=2.2Hz, 1H), 6.97-6.93 (m, 2H), 6.73 (d, J=2.2 Hz, 1H), 3.83 (s, 3H); LC-MS:method H, 2 to 98% B. RT=0.94 min, MS (ESI) m/z: 183.0 (M+H)⁺.

Intermediate 38C: 7-chlorobenzofuran-5-ol

To Intermediate 38B (0.32 g, 1.752 mmol) and tetrabutylammonium iodide(0.680 g, 1.840 mmol) in dichloromethane (4 mL) at −78° C. was added 1.0M boron trichloride in heptane (4.12 ml, 4.12 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 45 min. Then the coolingbath was removed and the reaction mixture was stirred at roomtemperature for 3.0 h. HPLC and TLC indicated a completion of thereaction. The mixture was poured into saturated sodium bicarbonate andice, stirred for 20 min, extracted with EtOAc. The organic layer wascollected, washed with 10% Na₂S₂O₃, water, brine and dried over sodiumsulfate. After evaporation of solvent, the crude product was dissolvedin a small amount of chloroform and charged to a 12 g silica gelcartridge which was eluted with hexanes for 1 min., then a 15 mingradient from 0% to 50% EtOAc in hexanes. The desired fractions werecombined and concentrated to give Intermediate 38C (0.29 g, 1.720 mmol,98% yield) as a slightly brown solid. ¹H NMR (400 MHz, chloroform-d) δ7.64 (d, J=2.0 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H),6.71 (d, J=2.2 Hz, 1H).

Intermediate 38D: tert-butyl((7-chlorobenzofuran-5-yl)oxy)dimethylsilane

To a stirred solution of Intermediate 38C (0.30 g, 1.780 mmol) in DMF(4.0 mL) was added TBDMS-Cl (0.402 g, 2.67 mmol) and imidazole (0.218 g,3.20 mmol). The reaction mixture was stirred at room temperature for 1.5h. HPLC and TLC indicated a completion of the reaction. The mixture waspartitioned between EtOAc/water. The organic layer was washed withwater, brine and dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 12 g silica gel cartridge which was eluted with hexanesfor 3 min., then a 15 min gradient from 0% to 15%. The desired fractionswere combined and concentrated to give Intermediate 38D (0.4 g, 1.414mmol, 79% yield) as a clear oil. ¹H NMR (400 MHz, chloroform-d) δ 7.64(d, J=2.2 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H), 6.72(d, J=2.2 Hz, 1H), 1.01 (s, 9H), 0.22 (s, 6H); LC-MS: method H, 2 to 98%B. RT=0.96 min, MS (ESI) m/z: MS not observed (M+H)⁺.

Intermediate 38E:tert-butyl((7-chloro-2-iodobenzofuran-5-yl)oxy)dimethylsilane

To diisopropylamine (0.302 mL, 2.121 mmol) in THF (4.0 mL) at −78° C.was added 1.6 N n-BuLi in hexanes (1.326 mL, 2.121 mmol). The reactionmixture was stirred at −78° C. for 20 min. Intermediate 38D (0.4 g,1.414 mmol) in THF (1.0 mL) was added dropwise, The reaction mixture wasstirred at −78° C. for 0.5 h. Iodine (0.610 g, 2.404 mmol) in THF (1.0mL) was added dropwise until the brown color persisted (ca 1.2 eq), andthe reaction mixture was stirred at −78° C. for 0.5 h, then at roomtemperature for 0.5 h. The reaction mixture was diluted with EtOAc,quenched with saturated ammonium chloride (5.0 mL) and 10% Na₂S₂O₃ (5.0mL). After stirring at room temperature for 10 min, the organic layerwas washed with brine, dried over sodium sulfate. After evaporation ofsolvent, Intermediate 38E (0.51 g, 1.148 mmol, 81% yield) was obtainedas a slightly brown oil. It was used for the next step without furtherpurification. ¹H NMR (400 MHz, chloroform-d) δ 6.89 (s, 1H), 6.84 (d,J=2.2 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 1.00 (s, 9H), 0.21 (s, 6H).LC-MS: method H, 2 to 98% B. RT=1.36 min, MS (ESI) m/z: no desired MSobserved (M+H)⁺.

Intermediate 38F5-(5-((tert-butyldimethylsilyl)oxy)-7-chlorobenzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline

To Intermediate I-1 (0.311 g, 1.223 mmol), Intermediate 38E (0.5 g,1.223 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.040 g, 0.049 mmol) was addedtoluene (4.5 mL) and EtOH (1.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (2M, 1.070mL, 2.141 mmol). The reaction mixture was heated in a microwave reactorat 120° C. for 30 min. HPLC and LCMS indicated a completion of thereaction. The crude reaction mixture was directly loaded on an ISCOcolumn for purification. The crude product was purified by flashchromatography (loading in chloroform, 0% to 25% EtOAc in hexane over 15min using a 24 g silica gel cartridge). The desired fractions werecombined and concentrated to yield Intermediate 38F (0.36 g, 0.733 mmol,59.9% yield) as an yellow solid. ¹H NMR (400 MHz, chloroform-d) δ 8.63(s, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.02 (s, 1H), 7.66 (dd, J=1.8, 0.9 Hz,1H), 7.65 (t, J_(HF)=71.75 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 6.88 (d,J=2.2 Hz, 1H), 2.66 (s, 3H), 1.02 (s, 9H), 0.23 (s, 6H); ¹⁹F NMR (376MHz, chloroform-d) δ −89.72 (s, 1F); LC-MS: method H, 2 to 98% B.RT=1.51 min, MS (ESI) m/z: 491.1 and 493.1 (M+H)⁺.

Intermediate 38G:7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-ol

To Intermediate 38F (0.36 g, 0.733 mmol) dissolved in THF (3.0 mL) andMeOH (3.0 mL) at room temperature was added 4.3 M sodium methoxide inMeOH (0.767 mL, 3.30 mmol). The reaction mixture was stirred at roomtemperature for 4.0 h. HPLC and LCMS indicated a completion of thereaction. The reaction mixture was quenched with 1.0 N HCl (2.93 mL,2.93 mmol), diluted with EtOAc. The organic layer was washed with brine,dried and concentrated to give Intermediate 38G (0.26 g, 0.687 mmol, 94%yield) as yellow solid. This was used for the next step without furtherpurification. ¹H NMR (400 MHz, chloroform-d) δ 8.43 (s, 1H), 8.08 (d,J=1.8 Hz, 1H), 7.90 (s, 1H), 7.57 (d, J=0.9 Hz, 1H), 6.90 (d, J=2.2 Hz,1H), 6.84-6.80 (m, 1H), 4.05 (s, 3H), 2.56 (s, 3H); LC-MS: method H, 2to 98% B. RT=1.14 min, MS (ESI) m/z: 341.0 and 343.0 (M+H)⁺.

Intermediate 38H2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethanol

To a suspension of Intermediate 38G (145 mg, 0.426 mmol) in DMF (3.0 mL)and THF (2.0 mL) was added cesium carbonate (277 mg, 0.851 mmol). Thereaction mixture was stirred at room temperature for 20 min. Then2-bromoethyl acetate (0.063 mL, 0.574 mmol) in THF (0.5 mL) was addeddropwise. The reaction mixture was stirred at room temperature for 30min, then at 65° C. for 1.5 h. HPLC and LCMS indicated completion ofreaction. After cooled to room temperature, the reaction mixture wasdiluted with EtOAc and water, extracted with EtOAc (6×). The combinedorganic layer was washed with brine and dried with sodium sulfate andconcentrated to give yellow solid as the acetate. The crude acetate wassuspended in a mixture of THF (3.0 mL) and MeOH (0.8 mL). To thissuspension was added 1.0 N NaOH (0.851 mL, 0.851 mmol). The reactionmixture was stirred at room temperature for 30 min. The suspensionturned to a clear brown solution. HPLC and LCMS indicated a cleanconversion of the ester to acid. The reaction was quenched with 1.0 NHCl (0.638 mL, 0.638 mmol) diluted in 1.0 mL of water, extracted withEtOAc, washed with saturated sodium bicarbonate, brine, dried oversodium sulfate and concentrated. The crude product was purified by flashchromatography (loading in chloroform, 10% to 60% EtOAc in hexane over10 min using a 12 g silica gel cartridge). The desired fractions werecombined and concentrated to yield Intermediate 38H (110 mg, 0.286 mmol,67.2% yield) as a lightly yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.67(s, 1H), 8.07 (s, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.70 (dd, J=1.8, 0.9 Hz,1H), 7.29 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 4.90 (t, J=5.5 Hz,1H), 4.07 (s, 3H), 4.06 (m, 2H), 3.78-3.74 (m, 2H), 2.61 (s, 3H); LC-MS:method H, 2 to 98% B. RT=1.14 min, MS (ESI) m/z: 385.0 and 387.0 (M+H).

Intermediate 38I2-{[7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)-1-benzofuran-5-yl]oxy}ethylchloroformate

To a solution Intermediate 38H (100 mg, 0.260 mmol) in THF (3.0 mL) atroom temperature was added 15% phosgene in toluene (0.733 mL, 1.039mmol). The reaction mixture was left stirring at room temperatureovernight. HPLC and LCMS indicated the reaction was complete. Solventwas completely removed under high vacuum to give Intermediate 38I (116mg, 0.259 mmol, 100% yield) as a slightly yellow solid. It was used forthe next step without purification. LC-MS: method H, 2 to 98% B. RT=1.30min, MS (ESI) m/z: 447.1 (M+H)⁺.

Example 38

To a solution of 2-methylpyridin-4-amine (19.34 mg, 0.179 mmol) in DCM(0.8 mL) was added DIEA (0.062 mL, 0.358 mmol), followed by addition ofIntermediate 38I (16 mg, 0.036 mmol) in THF (0.8 mL). The reactionmixture was stirred at room temperature for 1.0 h. HPLC and LCMSindicated a completion of reaction. The reaction was quenched byaddition of a small amount of MeOH/water/0.1% TFA. Solvent was removedunder vacuum. The crude material was purified via preparative LC/MS(method D, 50-90% B over 18 minutes, then a 5-minute hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to yield Example 38 (10 mg). ¹H NMR (500 MHz,DMSO-d₆) δ 10.37 (br. s., 1H), 8.68 (s, 1H), 8.29 (d, J=5.5 Hz, 1H),8.08 (s, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 7.39-7.32 (m, 3H), 7.16 (d,J=1.9 Hz, 1H), 4.51 (d, J=4.4 Hz, 2H), 4.34 (d, J=3.9 Hz, 2H), 4.07 (s,3H), 2.62 (s, 3H), 2.42 (s, 3H); LC-MS: method H, RT=2.16 min, MS (ESI)m/z: 519.2 (M+H)⁺. Analytical HPLC purity (method B): 99%.

Example 39N-(2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl)benzenesulfonamide

Intermediate 39A: tert-butyl(2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl)carbamate

A solution of tert-butyl (2-hydroxyethyl)carbamate (85 mg, 0.528 mmol)and DIAD (0.123 mL, 0.634 mmol) in THF (1.0 mL) was added dropwise to amixture of Intermediate 38G (72 mg, 0.211 mmol) and triphenylphosphine(163 mg, 0.623 mmol) in THF (2.0 mL) heated at 70° C. The reactionmixture was stirred at 70° C. for 15 min, at which time HPLC and LCMSindicated a completion of the reaction. Solvent was removed undervacuum. The crude product was purified by flash chromatography (loadingin chloroform, 5% to 45% EtOAc in hexane over 15 min using a 12 g silicagel cartridge). The desired fractions were combined and concentrated toyield Intermediate 39A (80 mg, 0.152 mmol, 72.0% yield) as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.05 (s, 1H), 8.04 (d,J=1.8 Hz, 1H), 7.68 (s, 1H), 7.25 (d, J=2.4 Hz, 1H), 7.06 (d, J=2.2 Hz,1H), 4.03-4.00 (m, 2H), 3.34 (t, J=5.6 Hz, 2H), 2.60 (s, 3H), 1.40 (s,9H); LC-MS: method H, 2 to 98% B. RT=1.29 min, MS (ESI) m/z:484.1(M+H)⁺.

Intermediate 39B2-((7-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethanamine

To Intermediate 39A (80 mg, 0.165 mmol) in DCM (2 mL) was added2,6-lutidine (0.077 mL, 0.661 mmol) followed by TMS-OTf (0.119 mL, 0.661mmol). The reaction mixture was stirred at room temperature for 1h. Themixture was diluted with EtOAc and NaHCO₃ and extracted with EtOAc. Thecombined organic layer was washed with brine and concentrated. Theresidual was treated with 1.0 ml of MeOH, stirred at room temperaturefor 15 min, and concentrated to give Intermediate 39B (60 mg) as yellowsolid. the crude sample was used for next step without purification.

Example 39

To a suspension of Intermediate 39B (18 mg, 0.047 mmol) in DMF (1.0 mL)and THF (1.0 mL) was added DIEA (0.066 mL, 0.375 mmol), followed bybenzenesulfonyl chloride (8.27 μl, 0.064 mmol). The reaction mixture wasstirred at room temperature for 2.0 h. Solvent was removed and the crudewas purified via preparative LC/MS (method D, 55-95% B over 10 minutes,then a 7-minute hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to yield 39(22.8 mg). ¹H NMR (500 MHz, chloroform-d) δ 8.51 (s, 1H), 8.16 (s, 1H),8.02 (s, 1H), 7.91 (d, J=7.7 Hz, 2H), 7.65 (s, 1H), 7.62-7.57 (m, 1H),7.55-7.50 (m, 2H), 6.91 (d, J=1.9 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 4.99(t, J=6.1 Hz, 1H), 4.12 (s, 3H), 4.03 (t, J=5.1 Hz, 2H), 3.42 (q, J=5.5Hz, 2H), 2.63 (s, 3H); LC-MS: method H, RT=2.66 min, MS (ESI) m/z: 524.2(M+H)⁺. Analytical HPLC purity (method B):100%.

Example 405-(benzo[b]thiophen-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline

To a solution of benzo[b]thiophen-2-yltributylstannane (35.1 mg, 0.083mmol) and Intermediate I-1G (20 mg, 0.069 mmol) in 1,4-dioxane (1 mL)was added Pd(Ph₃P)₄ (9.59 mg, 8.30 μmol). The mixture was heated at 150°C. for 1 h in a microwave reactor. LCMS indicated a completion of thereaction. The mixture was diluted with acetonitrile and filtered. Thefiltrate was concentrated and purified by a preparative HPLC (method A,65-100% B in 8 min.). The desired fractions were collected, dried andlyophilized to give 40 (18 mg, 0.050 mmol, 72.2% yield). ¹H NMR (400MHz, chloroform-d) δ 8.66 (s, 1H), 8.07 (s, 1H), 8.00-7.46 (m, 5H),7.45-7.32 (m, 2H), 2.64 (s, 3H). ¹⁹F NMR (376 MHz, chloroform-d) δ−90.43 (s, 2F). LC-MS: method B, RT=2.55 min, MS (ESI) m/z: 343.0(M+H)⁺. Analytical HPLC purity (method A): 99%.

Example 412-(difluoromethoxy)-5-(7-methoxybenzofuran-2-yl)-7-methylquinoxaline

To (7-methoxybenzofuran-2-yl)boronic acid (13.28 mg, 0.069 mmol) andIntermediate I-1G was added toluene (0.75 mL) and EtOH (0.25 mL). Thereaction mixture was stirred at room temperature until solids aredissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (6.78 mg, 8.30 μmol) was added.The flask was degassed and flushed with argon. Finally sodium carbonate2M (0.069 mL, 0.138 mmol) was added dropwise. The reaction vessel wassealed and bubbled with argon for 5 min, then placed in microwavereactor at 140° C. for 30 min. The reaction mixture was cooled to roomtemperature, diluted with EtOAc and water, extracted with EtOAc (3×).The combined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude sample was purified by 12 g ISCO column elutedwith 0-70% EtOAc in hexane for 15 min. The desired fraction wascollected, dried and purified by preparative HPLC (method A, 30-100% Bin 10 min.) to give Example 41 (8 mg, 0.022 mmol, 31.5% yield). ¹H NMR(400 MHz, chloroform-d) δ 8.66 (s, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.10 (s,1H), 7.91-7.47 (m, 2H), 7.29 (s, 1H), 7.23-7.17 (m, 1H), 6.88 (d, J=7.8Hz, 1H), 4.10 (s, 3H), 2.65 (s, 3H). ¹⁹F NMR (376 MHz, chloroform-d)−90.12 (s, 2F). LC-MS: method B, RT=2.53 min, MS (ESI) m/z: 357.0(M+H)⁺. Analytical HPLC purity (method A): 98%.

Example 422-(difluoromethoxy)-5-(4-methoxybenzofuran-2-yl)-7-methylquinoxaline

Intermediate 42A: (benzofuran-4-yloxy)(tert-butyl)dimethylsilane

To a solution of benzofuran-4-ol (200 mg, 1.491 mmol) in DMF (5 mL) wasadded TBDMS-Cl (337 mg, 2.237 mmol) and imidazole (203 mg, 2.98 mmol).The mixture was stirred at room temperature for 2 h. LCMS indicated acompletion of the reaction. The mixture was diluted by EtOAc and water,extracted with EtOAc, the combined organic layer was washed with brine,dried with MgSO₄ and concentrated. The crude sample was purified with a12 g ISCO column eluted with 0-50% EtOAc/Hex, the desired fraction wascollected to give Intermediate 42A (270 mg, 1.087 mmol, 72.9% yield). ¹HNMR (400 MHz, chloroform-d) δ 7.53 (d, J=2.3 Hz, 1H), 7.18-7.10 (m, 2H),6.79 (d, J=1.8 Hz, 1H), 6.72-6.60 (m, 1H), 1.06 (s, 10H), 0.31-0.18 (m,6H). LC-MS: method B, RT=2.55 min, MS (ESI) m/z: 249 (M+H)⁺.

Intermediate 42B: 4-(tert-butyldimethylsilyloxy)benzofuran-2-ylboronicacid

To a solution of Intermediate 42A (270 mg, 1.087 mmol) in THF (4 mL) wasadded n-BuLi (0.815 mL, 1.304 mmol) at −78° C. After 30 min stirring,trimethyl borate (0.243 mL, 2.174 mmol) was added, and the reactionmixture was slowly warmed up to room temperature over 1h. HCl (5.43 mL,5.43 mmol) was added and the mixture was stirred at room temperature for30 min. The mixture was diluted with EtOAc and water, extracted withEtOAc and the combined organic layer was washed with brine, dried withMgSO₄ and concentrated. The crude sample was purified with a 12 g ISCOcolumn eluted with 0-70% EtOAc/Hex. The desired fraction was collectedto give Intermediate 42B (190 mg, 0.650 mmol, 59.8% yield). LC-MS:method C, RT=2.35 min, MS (ESI) m/z: 293 (M+H)⁺.

Intermediate 42C5-(4-(tert-butyldimethylsilyloxy)benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline

To Intermediate I-1 (50 mg, 0.173 mmol) and Intermediate 42B (60.7 mg,0.208 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The reactionmixture was stirred at room temperature until solids are dissolved, then[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (16.95 mg, 0.021 mmol) was added. The flaskwas degassed and flushed with argon. Finally sodium carbonate (0.173 mL,2M, 0.346 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 120°C. for 30 min. LCMS indicated a completion of the reaction. The reactionmixture was cooled to room temperature and was diluted with EtOAc andwater, extracted with EtOAc (3×), the combined organic layer was washedwith brine, dried with MgSO₄ and concentrated. The crude sample waspurified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for15 min. The desired fraction was collected to give Intermediate 42C (79mg, 0.173 mmol, 100% yield). ¹H NMR (400 MHz, chloroform-d) δ 8.66 (s,1H), 8.23 (d, J=1.8 Hz, 1H), 8.09 (s, 1H), 7.88-7.47 (m, 2H), 7.23-7.18(m, 2H), 6.69 (dd, J=6.3, 2.3 Hz, 1H), 2.65 (s, 3H), 1.12-1.09 (m, 9H),0.29 (s, 6H). ¹⁹F NMR (376 MHz, acetonitrile-d₃) δ −90.43 (s, 2F).LC-MS: method C, RT=2.68 min.

Intermediate 42D:2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-4-ol

To a solution of Intermediate 42C (76 mg, 0.166 mmol) in MeOH (1 mL) andTHF was added HCl (0.277 mL, 12M, 3.33 mmol). The mixture was stirred atroom temperature for 1h. LCMS indicated a completion of the reaction.The mixture was diluted with EtOAc and saturated NaHCO₃, extracted withEtOAc, the combined organic layer was washed with brine, dried withMgSO₄ and concentrated. Intermediate 42D (50 mg, 0.142 mmol, 85% yield)was obtained and used for next step without purification. ¹H NMR (400MHz, chloroform-d) δ 8.65 (s, 1H), 8.25 (d, J=1.8 Hz, 1H), 8.20 (s, 1H),7.87-7.47 (m, 2H), 7.23-7.18 (m, 2H), 6.72-6.65 (m, 1H), 2.66 (s, 3H).¹⁹F NMR (376 MHz, chloroform-d) −90.12 (s, 2F). LC-MS: method B, RT=4.44min, MS (ESI) m/z: 343.1 (M+H)⁺.

Example 42

To a solution of Intermediate 42D (10 mg, 0.029 mmol) in acetonitrile (1mL) was added Cs₂CO₃ (28.6 mg, 0.088 mmol) and MeI (1.827 μl, 0.029mmol). The mixture was stirred at 45° C. for 1 h. The mixture wasdiluted with 1 ml of DMSO and 1 ml of acetonitrile, filtered andpurified with a preparative HPLC (method A, 65-100% B in 8 min.). Thedesired fractions were placed in a SpeedVac overnight to remove solvent,then lyophilized to give Example 42 (5.6 mg, 0.015 mmol, 52.7% yield).¹H NMR (chloroform-d, 400 MHz): δ=8.65 (s, 1H), 8.25 (s, 1H), 8.20 (s,1H), 7.46-7.86 (m, 2H), 7.28-7.32 (m, 1H), 7.19-7.23 (m, 1H), 6.71 (d,J=7.8 Hz, 1H), 4.02 (s, 3H), 2.65 ppm (s, 3H). ¹⁹F NMR (chloroform-d,400 MHz) −90.12 (s, 2F). LC-MS: method B, RT=4.56 min, MS (ESI) m/z:357.1 (M+H)⁺. Analytical HPLC purity (method A): 98%.

Example 435-(4-(benzyloxy)benzofuran-2-yl)-2-methoxy-7-methylquinoxaline

To a solution of Intermediate 42D (10 mg, 0.029 mmol) in acetonitrile (1mL) was added Cs₂CO₃ (28.6 mg, 0.088 mmol) and benzyl bromide (3.47 μl,0.029 mmol). The mixture was stirred at 45° C. for 1 h. The mixture wasdiluted with 1.0 ml of MeOH and water, extracted with EtOAc. Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The mixture was purified with preparative HPLC (method A,65-100% B in 6 min.). The desired fractions were placed in a SpeedVacovernight to remove solvent, then lyophilized to give 43 (2.5 mg, 5.86μmol, 20.07% yield). ¹H NMR (chloroform-d, 400 MHz): δ=8.53 (s, 1H),8.19 (s, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.62 (s, 1H), 7.49-7.57 (m, 2H),7.40-7.47 (m, 2H), 7.33-7.39 (m, 1H), 7.21-7.25 (m, 2H), 6.72-6.80 (m,1H), 5.28 (s, 2H), 4.12 (s, 3H), 2.63 ppm (s, 3H). LC-MS: method C,RT=3.25 min, MS (ESI) m/z: 397.1 (M+H)⁺. Analytical HPLC purity (methodA): 93.0%.

Example 445-(5-(benzyloxy)benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline

Intermediate 44A: benzofuran-5-ol

To an ice-cooled solution of 5-methoxybenzofuran (0.71 g, 4.79 mmol) indichloromethane (8.0 mL) was added 1.0 M boron tribromide indichloromethane (4.79 mL, 4.79 mmol). The mixture was stirred at 0° C.for 1.0 h. HPLC indicated ca 30-40% starting material still remaining.Then another portion of 1.0 M boron tribromide in dichloromethane (4.79mL, 4.79 mmol) was added and the mixture was stirred from 0° C. to roomtemperature over an hour. HPLC indicated a complete conversion ofstarting material. The mixture was poured into ice water, stirred for 15min, extracted with dichloromethane. The organic layer was dried oversodium sulfate. After evaporation of solvent, Intermediate 44A (0.33 g,2.460 mmol, 51.3% yield) was obtained as slightly brown oil. It was usedfor the next step without further purification. ¹H NMR (500 MHz,chloroform-d) δ 7.60 (d, J=2.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.02 (d,J=2.5 Hz, 1H), 6.82 (dd, J=8.8, 2.8 Hz, 1H), 6.69-6.67 (m, 1H), 4.78 (s,1H); LC-MS: Method A, 50 to 100% B. RT=2.32 min, MS (ESI) m/z: no(M+H)⁺.

Intermediate 44B: (benzofuran-5-yloxy)(tert-butyl)dimethylsilane

To a stirred solution of Intermediate 44A (0.33 g, 2.460 mmol) in DMF(8.0 mL) was added TBDMS-Cl (0.519 g, 3.44 mmol) and imidazole (0.285 g,4.18 mmol). The reaction mixture was left stirring at room temperaturefor 2.0 h. The mixture was partitioned between EtOAc/water. The organiclayer was washed with brine, dried over sodium sulfate. Afterevaporation of solvent, the crude product was dissolved in a smallamount of chloroform and charged to a 24 g silica gel cartridge whichwas eluted with hexanes for 3 min., then a 15 min gradient from 0% to20% EtOAc in hexanes. The desired fractions were combined andconcentrated to give Intermediate 44B (0.48 g, 1.932 mmol, 79% yield) asa clear oil. ¹H NMR (500 MHz, chloroform-d) δ 7.60 (d, J=1.9 Hz, 1H),7.36 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.83 (dd, J=8.7, 2.3 Hz,1H), 6.70-6.69 (m, 1H), 1.03 (s, 9H), 0.23 (s, 6H); LC-MS: Method A, 50to 100% B. RT=2.19 min, MS (ESI) m/z: 249 (M+H)⁺.

Intermediate 44C: 5-(tert-butyldimethylsilyloxy)benzofuran-2-ylboronicacid

To Intermediate 44B (0.48 g, 1.932 mmol) in THF (7.0 mL) at −78° C. wasadded 1.6 N n-BuLi in hexanes (1.993 mL, 3.19 mmol) dropwise. Thesolution turned to brown. The mixture was stirred at −78° C. for 10 min,followed by addition of triisopropyl borate (1.346 mL, 5.80 mmol). Themixture was stirred for 20 min, and the cooling bath was removed toallow warm up to room temperature over 0.5 h. It was diluted with EtOAc,quenched with 20 mL of 0.5 N HCl. After stirring at room temperature for10 min, the organic layer was collected, washed with brine, dried oversodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 12 g silicagel cartridge which was eluted with hexanes for 3 min., then a 12 mingradient from 0% to 60% EtOAc in hexanes. The desired fractions werecombined, concentrated and lyophilized to give Intermediate 44C (0.416g, 1.424 mmol, 73.7% yield) as a white solid. ¹H NMR (500 MHz,methanol-d₄) δ 7.39 (d, J=8.8 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=2.5 Hz,1H), 6.88 (dd, J=8.8, 2.5 Hz, 1H), 1.03 (s, 9H), 0.22 (s, 6H); LC-MS:Method A, 0 to 100% B. RT=2.30 min, MS (ESI) m/z: 293.1 (M+H)⁺.

Intermediate 44D:2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-ol

A mixture of Intermediate I-1G (324 mg, 1.122 mmol), Intermediate 44C(410 mg, 1.403 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (36.7 mg, 0.045 mmol) in toluene (6 mL) andEtOH (2.000 mL) was degassed with argon for 2.0 min. To this solutionwas added sodium carbonate (2.0 M, 0.982 mL, 1.964 mmol). The mixturewas then heated in an oil bath at 85° C. overnight. The crude reactionmixture was diluted with EtOAc/water. The organic layer was collected,dried over sodium sulfate. After evaporation of solvent, the crudeproduct was obtained as brown oil that solidified when treated withMeOH. It was used for the next step without further purification.

To the crude product obtained above (0.55 g, 1.205 mmol) in MeOH (4.0mL) and THF (4.00 mL) was added 12 N HCl (1.004 mL, 12.05 mmol). Themixture was stirred at room temperature for 30 min. TLC indicated ca 40%starting material remaining. Another portion of 12 N HCl (1.004 mL,12.05 mmol) was added. The reaction was continued at room temperaturefor 1.5 h. TLC indicated a clean reaction. Methanol was removed undervacuum, the crude was diluted with EtOAc, washed with water and brine.The organic layer was collected, dried over sodium sulfate. Afterevaporation of solvent, the crude product was dissolved in a smallamount of chloroform/THF and charged to a 12 g silica gel cartridgewhich was eluted with hexanes for 3 min., then a 10 min gradient from 0%to 60% EtOAc in hexanes. The desired fractions were combined andconcentrated to give Intermediate 44D (0.423 g, 1.236 mmol, 103% yield)as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.90 (s,1H), 8.21 (d, J=1.7 Hz, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.89 (t,J_(HF)=71.53 Hz, 1H), 7.75 (dd, J=1.9, 1.1 Hz, 1H), 7.47 (d, J=8.8 Hz,1H), 7.08 (d, J=2.5 Hz, 1H), 6.84 (dd, J=8.8, 2.5 Hz, 1H), 2.63 (s, 3H);¹⁹F NMR (471 MHz, DMSO-d₆) δ −87.80 (s, 2F); LC-MS: Method A, 0 to 100%B. RT=2.30 min, MS (ESI) m/z: 343.0 (M+H)⁺.

Example 44

To a solution of Intermediate 44D (20 mg, 0.058 mmol) in acetonitrile (1mL) was added Cs₂CO₃ (57.1 mg, 0.175 mmol) and (bromomethyl)benzene (100mg, 0.584 mmol). The mixture was stirred at 45° C. for 1 h. The mixturewas diluted with 1 ml of DMSO and 1 ml of acetonitrile and filtered. Thefiltrate was purified with a preparative HPLC (method A, 65-100% B in 8min.). The desired fractions were placed in a SpeedVac overnight toremove solvent, then lyophilized to give Example 44 (17 mg, 0.037 mmol,63.9% yield). ¹H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 8.22 (s,1H), 8.01 (s, 1H), 7.66-7.34 (m, 8H), 7.20 (d, J=2.2 Hz, 1H), 7.07-7.02(m, 1H), 5.14 (s, 2H), 2.64 (s, 3H). ¹⁹F NMR (chloroform-d, 400 MHz):)−90.12 (s, 2F). LC-MS: method C, RT=2.84 min, MS (ESI) m/z: 433.0(M+H)⁺. Analytical HPLC purity (method A): 100%.

Example 452-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-2-yl)-7-methylquinoxaline

To 2-bromoimidazo[1,2-a]pyridine (17.58 mg, 0.089 mmol) and IntermediateI-1 (20 mg, 0.059 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL).The reaction mixture was stirred at room temperature until solids aredissolved, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.83 mg, 7.14 μmol) was added.The flask was degassed and flushed with argon. Finally sodium carbonate(0.059 mL, 2M, 0.119 mmol) was added dropwise. The reaction vessel wassealed and bubbled with argon for 5 min, then placed in microwavereactor at 120° C. for 30 min. The reaction mixture was cooled to roomtemperature and was diluted with EtOAc and water, extracted with EtOAc(3×). The combined organic layer was washed with brine, dried with MgSO₄and concentrated. The crude sample was purified with a preparative HPLC(method A, 30-100% B in 10 min.). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to give Example45 (6.5 mg, 0.019 mmol, 32.1% yield). ¹H NMR (400 MHz, acetonitrile-d₃)δ 8.90 (br. s., 1H), 8.71 (br. s., 1H), 8.58 (d, J=6.8 Hz, 1H), 8.43 (s,1H), 8.03 (br. s., 1H), 7.50 (s, 2H), 7.31 (t, J=6.8 Hz, 1H), 2.63 (s,3H). ¹⁹F NMR (376 MHz, acetonitrile-d₃) δ −90.60 (br. s., 2F). LC-MS:method C, RT=1.66 min, MS (ESI) m/z: 327.0 (M+H)⁺. Analytical HPLCpurity (method A): 99%.

Example 46 Methyl2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethylcarbamate

Intermediate 46A: tert-butyl2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethylcarbamate

To a solution of triphenylphosphine (53.6 mg, 0.205 mmol) in THF (1.0mL) at 0° C., was added DIAD (0.040 mL, 0.205 mmol) dropwise. Themixture was stirred at 0° C. for 10 min. A solution of Intermediate 44D(35 mg, 0.102 mmol) and tert-butyl (2-hydroxyethyl)carbamate (33.0 mg,0.205 mmol) in THF (1.0 mL) was added dropwise. The mixture was stirredat 0° C. to room temperature for 30 min, then heated up to 55° C.overnight. After evaporation of solvent, the crude was dissolved inDMSO/acetonitrile (1.5 mL/1.5 mL) and purified using a preparative HPLC(method A, 30-100% B in 10 min.). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to giveIntermediate 46A (18 mg, 0.037 mmol, 36.3% yield) as a yellowlyophilate. ¹H NMR (chloroform-d, 400 MHz): δ=8.65 (s, 1H), 8.25 (s,1H), 8.04 (s, 1H), 7.40-7.91 (m, 3H), 7.13 (d, J=2.5 Hz, 1H), 6.90-7.03(m, 1H), 5.05 (br. s., 1H), 4.02-4.20 (m, 2H), 3.59 (br. s., 2H), 2.66(s, 3H), 1.48 ppm (s, 9H). ¹⁹F NMR (chloroform-d, 376 MHz): δ=−90.15 ppm(s, 2F). LC-MS: method B, RT=2.58 min, MS (ESI) m/z: 486.1 (M+H)⁺.

Intermediate 46B2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethanamine

To a solution of Intermediate 46A (13 mg, 0.027 mmol) in DCM (2 mL) wasadded TFA (0.206 mL, 2.68 mmol) and the mixture was stirred at roomtemperature overnight. Solvent was removed. The residual was purifiedwith a preparative HPLC (method A, 30-100% B in 10 min.). The desiredfractions were placed in a SpeedVac overnight to remove solvent, thenlyophilized to give Intermediate 46B (8 mg, 0.020 mmol, 75% yield). ¹HNMR (acetonitrile-d₃, 400 MHz): δ=8.71 (s, 1H), 8.25 (s, 1H), 8.06 (s,1H), 7.49-7.89 (m, 3H), 7.27 (d, J=2.5 Hz, 1H), 7.03 (dd, J=8.8, 2.5 Hz,1H), 4.27 (t, J=4.8 Hz, 2H), 3.40 (t, J=4.9 Hz, 2H), 2.65 ppm (s, 3H).¹⁹F NMR (acetonitrile-d₃, 376 MHz): δ=−76.15 (br. s., 3F), −90.48 ppm(s, 2F). LC-MS: method C, RT=2.02 min, MS (ESI) m/z: 386.0 (M+H)⁺.Analytical HPLC purity (method A): 98%.

Example 46

To a suspension of Intermediate 46B (6.5 mg, 0.013 mmol) in DCM (1 mL)was added Et₃N (9.07 μl, 0.065 mmol) followed by methyl chloroformate(2.016 μl, 0.026 mmol). The mixture was stirred at room temperature for1 h. Solvent was removed and the residual was purified with apreparative HPLC (method A, 50-100% B in 8 min.). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto give Example 46 (4.0 mg, 8.75 μmol, 67.2% yield). ¹H NMR(acetonitrile-d₃, 400 MHz): δ=8.71 (s, 1H), 8.25 (d, J=1.8 Hz, 1H), 8.04(s, 1H), 7.44-7.91 (m, 3H), 7.23 (d, J=2.5 Hz, 1H), 6.98 (dd, J=8.8, 2.5Hz, 1H), 4.08 (t, J=5.6 Hz, 2H), 3.61 (s, 3H), 3.50 (q, J=5.7 Hz, 2H),2.64 ppm (s, 3H). ¹⁹F NMR (acetonitrile-d₃, 376 MHz): δ=−90.47 ppm (s,2F). LC-MS: method C, RT=2.42 min, MS (ESI) m/z: 444.1 (M+H)⁺.Analytical HPLC purity (method A): 98%.

Example 475-(1H-benzo[d]imidazol-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline

To 2-chloro-1H-benzo[d]imidazole (10.89 mg, 0.071 mmol) and IntermediateI-1 (20 mg, 0.059 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL).The mixture was stirred at room temperature until solids are dissolved,then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex with dichloromethane (1:1) (5.83 mg, 7.14 μmol) was added. Theflask was degassed and flushed with argon. Finally sodium carbonate(0.045 mL, 2M, 0.089 mmol) was added dropwise. The reaction vessel wassealed and bubbled with argon for 5 min, then placed in microwavereactor at 120° C. for 30 min, then at 140° C. for 20 min. The reactionmixture was cooled to room temperature and was diluted with EtOAc andwater, extracted with EtOAc (3×). The combined organic layer was washedwith brine, dried with MgSO₄ and concentrated. The crude sample waspurified with a preparative HPLC (method A, 20-100% B in 8 min.). Thedesired fractions were placed in a SpeedVac overnight to remove solvent,then lyophilized to give Example 47 (10 mg, 0.030 mmol, 50.5% yield). ¹HNMR (acetonitrile-d₃, 400 MHz): δ=8.85 (d, J=1.5 Hz, 1H), 8.79 (br. s.,1H), 7.46-7.93 (m, 6H), 2.66 ppm (s, 3H). ¹⁹F NMR (376 MHz,acetonitrile-d₃) δ −90.69 (s, 2F). LC-MS: method C, RT=1.71 min, MS(ESI) m/z: 327.1 (M+H)⁺. Analytical HPLC purity (method A): 98%.

Example 482-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazole

To 2-chloro-6-methoxybenzo[d]thiazole (14.26 mg, 0.071 mmol) andIntermediate I-1 (20 mg, 0.059 mmol) was added toluene (0.75 mL) andEtOH (0.25 mL). The mixture was stirred at room temperature until solidsare dissolved, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (5.83 mg, 7.14 μmol) was added. The flask wasdegassed and flushed with argon. Finally sodium carbonate (0.045 mL, 2M,0.089 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 120°C. for 30 min. The reaction mixture was cooled to room temperature andwas diluted with EtOAc and water, extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude sample was purified with a preparative HPLC(method A, 65-100% B in 8 min.). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to give Example48 (12.5 mg, 0.033 mmol, 55.1% yield). ¹H NMR (acetonitrile-d₃, 400MHz): δ=8.70-8.83 (m, 2H), 7.95-8.04 (m, 1H), 7.48-7.90 (m, 3H),7.12-7.21 (m, 1H), 3.90 (s, 3H), 2.69 ppm (s, 3H). ¹⁹F NMR(acetonitrile-d₃, 400 MHz):) −90.12 (s, 2F). LC-MS: method C, RT=2.50min, MS (ESI) m/z: 374.0 (M+H)⁺. Analytical HPLC purity (method A): 98%.

Example 49 tert-butyl2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)acetate

To a solution of Intermediate 44D (20 mg, 0.058 mmol) in DMF (1 mL) wasadded Cs₂CO₃ (57.1 mg, 0.175 mmol) and tert-butyl 2-bromoacetate (57.0mg, 0.292 mmol). The mixture was stirred at 100° C. for 2 h. The mixturewas diluted with 1 ml of DMSO and 1 ml of acetonitrile, filtered. Thefiltrate was purified with a preparative HPLC (method A, 65-100% B in 6min.). The desired fractions were placed in a SpeedVac overnight toremove solvent, then lyophilized to give Example 49 (20 mg, 0.043 mmol,73.5% yield). ¹H NMR (chloroform-d, 400 MHz): δ=8.64 (s, 1H), 8.23 (d,J=1.5 Hz, 1H), 8.02 (s, 1H), 7.42-7.86 (m, 3H), 7.12 (d, J=2.5 Hz, 1H),7.01 (dd, J=8.8, 2.5 Hz, 1H), 4.59 (s, 2H), 2.65 (s, 3H), 1.50-1.56 ppm(m, 9H). ¹⁹F NMR (chloroform-d, 376 MHz): δ=−90.15 ppm (s, 2F). LC-MS:method C, RT=2.61 min, MS (ESI) m/z: 457.1 (M+H)⁺. Analytical HPLCpurity (method A): 100%.

Example 502-(difluoromethoxy)-5-(5-methoxy-1H-benzo[d]imidazol-2-yl)-7-methylquinoxaline

To 2-chloro-5-methoxy-1H-benzo[d]imidazole (13.04 mg, 0.071 mmol) andIntermediate I-1 (20 mg, 0.059 mmol) was added toluene (0.75 mL) andEtOH (0.25 mL). The reaction mixture was stirred at room temperatureuntil solids are dissolved, then[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (5.83 mg, 7.14 μmol) was added. The flask wasdegassed and flushed with argon. Finally sodium carbonate (0.059 mL, 2M,0.119 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 140°C. for 30 min. The reaction mixture was cooled to room temperature andwas diluted with EtOAc and water, extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude sample was purified with a preparative HPLC(method A, 30-100% B in 8 min.). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to give Example50 (6 mg, 0.016 mmol, 27.5% yield). ¹H NMR (acetonitrile-d₃, 400 MHz):δ=8.77 (br. s., 2H), 7.70 (s, 3H), 7.27-7.39 (m, 1H), 7.05-7.18 (m, 1H),3.90 (s, 3H), 2.65 ppm (s, 3H). ¹⁹F NMR (acetonitrile-d₃, 376 MHz):δ=−76.64 (br. s., 3F), −90.69 ppm (s, 2F). LC-MS: method C, RT=1.78 min,MS (ESI) m/z: 357.0 (M+H)⁺. Analytical HPLC purity (method A): 98%

Example 512-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methoxybenzo[d]thiazole

Intermediate 51A: 2-bromo-4-methoxybenzo[d]thiazole

To a suspension of 4-methoxybenzo[d]thiazol-2-amine (2.5 g, 13.87 mmol)and p-TSA monohydrate (7.92 g, 41.6 mmol) in acetonitrile (80 mL) at 10°C. (cooled with ice water) was added dropwise a solution of sodiumnitrite (1.914 g, 27.7 mmol) and potassium bromide (4.13 g, 34.7 mmol)in water (5 ml) over a period of 25 min. The reaction mixture wasstirred at 10° C. for 10 min, and allowed to warm up to room temperatureand stirred for 2.0 h. HPLC indicated a completion of reaction. To thereaction mixture was added sodium bicarbonate (pH to 9.0), water andEtOAc. The organic layer was collected, washed with water, saturatedNa₂S₂O₃, water, brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 120 g silica gel cartridge which was eluted withhexanes for 4 min., then an 18 min gradient from 0% to 40% EtOAc inhexanes. The desired fractions were combined and concentrated to giveIntermediate 51A (2.51 g, 10.28 mmol, 74.1% yield) as a slightly yellowsolid. ¹H NMR (500 MHz, chloroform-d) δ 7.40-7.37 (m, 2H), 6.92 (dd,J=6.3, 2.5 Hz, 1H), 4.06 (s, 3H); LC-MS: method A, RT=1.79 min, MS (ESI)m/z: 244.0 and 246.0 (M+H)⁺.

Example 51

To Intermediate 51A (10 mg, 0.041 mmol) and Intermediate I-1 (20.66 mg,0.061 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixturewas stirred at room temperature until solids are dissolved, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (4.01 mg, 4.92 μmol) was added. The flask wasdegassed and flushed with argon. Finally sodium carbonate (0.031 mL, 2M,0.061 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 120°C. for 30 min. LCMS indicated a completion of the reaction. The reactionmixture was cooled to room temperature and was diluted with EtOAc andwater, extracted with EtOAc (3×). The combined organic layer was washedwith brine, dried with MgSO₄ and concentrated. The crude sample waspurified with a preparative HPLC (method A, 50-100% B in 8 min.). Thedesired fractions were placed in a SpeedVac overnight to remove solvent,then lyophilized to give Example 51 (2.5 mg, 6.43 μmol, 15.69% yield).¹H NMR (400 MHz, chloroform-d) δ 8.93 (d, J=1.65 Hz, 1H), 8.71 (s, 1H),7.80 (s, 1H), 7.58 (d, J=8.25 Hz, 1H), 7.47-7.86 (m, 1H), 7.39 (t,J=7.97 Hz, 1H), 6.96 (d, J=7.70 Hz, 1H), 4.13 (s, 3H), 2.68 (s, 3H). ¹⁹FNMR (376 MHz, chloroform-d) δ −89.62 (s, 2F). LC-MS: method C, RT=2.45min, MS (ESI) m/z: 374.0 (M+H)⁺. Analytical HPLC purity (method A): 97%.

Example 522-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole

Intermediate 52A: 2-bromo-4-methylbenzo[d]thiazole

To a white suspension of 4-methylbenzo[d]thiazol-2-amine (0.5 g, 3.04mmol) and p-TSA monohydrate (1.737 g, 9.13 mmol) in acetonitrile (20 mL)at 10° C. (cooled with ice water) was added dropwise a solution ofsodium nitrite (0.420 g, 6.09 mmol) and potassium bromide (0.906 g, 7.61mmol) in water (5 mL) over a period of 25 min. The reaction mixture wasstirred at 10° C. for 10 min, and allowed to warm up to room temperatureand stirred for 1.0 h. To the reaction mixture was added sodiumbicarbonate (pH to 9.0), water and EtOAc. The organic layer wascollected, washed with water, saturated Na₂S₂O₃, water, brine, driedover sodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 40 g ISCOcolumn which was eluted with hexanes for 2 min., then a 20 min gradientfrom 0% to 40% EtOAc in hexanes. The desired fractions were combined andconcentrated to give Intermediate 52A (640 mg, 2.81 mmol, 92% yield) asa yellow solid. ¹H NMR (400 MHz, chloroform-d) δ 7.62 (td, J=0.69, 7.71Hz, 1H), 7.21-7.34 (m, 3H), 2.71 (s, 3H). LC-MS: method C, RT=2.11 min,MS (ESI) m/z: 227.0 and 229.0 (M+H)⁺.

Example 52

To Intermediate 52A (17 mg, 0.074 mmol) and Intermediate I-1 (30 mg,0.089 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixturewas stirred at room temperature until solids are dissolved, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (7.29 mg, 8.92 μmol) was added. The flask wasdegassed and flushed with argon. Finally sodium carbonate (0.056 mL, 2M,0.112 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 120°C. for 30 min. The reaction mixture was cooled to room temperature andwas diluted with EtOAc and water, extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude sample was purified with a preparative HPLC(method A, 65-100% B in 8 min.). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to give Example52 (11.5 mg, 0.031 mmol, 41.5% yield). ¹H NMR (400 MHz, chloroform-d) δ8.86 (d, J=1.52 Hz, 1H), 8.71 (s, 1H), 7.47-7.90 (m, 3H), 7.30-7.36 (m,2H), 2.90 (s, 3H), 2.72 (s, 3H). ¹⁹F NMR (400 MHz, chloroform-d) δ−90.12 (s, 2F). LC-MS: method C, RT=2.68 min, MS (ESI) m/z: 358.0(M+H)⁺. Analytical HPLC purity (method A): 98%.

Example 532-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazole

Intermediate 53A: 2-bromo-4-fluorobenzo[d]thiazole

To a suspension of 4-fluorobenzo[d]thiazol-2-amine (0.52 g, 3.09 mmol)and p-TSA monohydrate (1.764 g, 9.28 mmol) in acetonitrile (20 mL) at10° C. (cooled with ice water) was added dropwise a solution of sodiumnitrite (0.427 g, 6.18 mmol) and potassium bromide (0.920 g, 7.73 mmol)in water (5 mL) over a period of 25 min. The reaction mixture wasstirred at 10° C. for 10 min, and allowed to warm up to room temperatureand stirred for 1.0 h. To the reaction mixture was added sodiumbicarbonate (pH to 9.0), water and EtOAc. The organic layer wascollected, washed with water, saturated Na₂S₂O₃, water, brine, driedover sodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 40 g ISCOcolumn which was eluted with hexanes for 2 min., then a 20 min gradientfrom 0% to 40% EtOAc in hexanes. The desired fractions were combined andconcentrated to give Intermediate 53A (640 mg, 2.76 mmol, 89% yield) asa yellow solid. ¹H NMR (400 MHz, chloroform-d) δ 7.59 (dd, J=0.76, 8.08Hz, 1H), 7.40 (dt, J=4.55, 8.08 Hz, 1H), 7.20 (ddd, J=1.01, 8.08, 10.11Hz, 1H). LC-MS: method C, RT=1.84 min, MS (ESI) m/z: 231.9 and 233.9(M+H)⁺.

Example 53

To Intermediate 53A (17.26 mg, 0.074 mmol) and Intermediate I-1 (30 mg,0.089 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixturewas stirred at room temperature until solids are dissolved, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (7.29 mg, 8.92 μmol) was added. The flask wasdegassed and flushed with argon. Finally sodium carbonate (0.056 mL, 2M,0.112 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 120°C. for 30 min. The reaction mixture was cooled to room temperature andwas diluted with EtOAc and water, extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude sample was purified with a preparative HPLC(method A, 50-100% B in 6 min.). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to give Example53 (15.0 mg, 0.039 mmol, 53.0% yield). ¹H NMR (400 MHz, chloroform-d) δ8.92 (d, J=1.77 Hz, 1H), 8.71 (s, 1H), 7.84 (dd, J=0.88, 1.89 Hz, 1H),7.76 (dd, J=0.88, 7.96 Hz, 1H), 7.48-7.87 (m, 1H), 7.39 (dt, J=4.67,8.02 Hz, 1H), 7.23 (ddd, J=1.01, 7.96, 10.48 Hz, 1H), 2.71 (s, 3H). ¹⁹FNMR (400 MHz, chloroform-d) −90.12 (s, 2F). LC-MS: method C, RT=2.53min, MS (ESI) m/z: 362.0 (M+H)⁺. Analytical HPLC purity (method A): 96%.

Example 542-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)-N-methylethanamine

Intermediate 54A: tert-butyl2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethyl(methyl)carbamate

A solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (41.0 mg,0.234 mmol) and DIAD (0.057 mL, 0.292 mmol) in THF (1.0 mL) was added toa mixture of Intermediate 44D (20 mg, 0.058 mmol) and triphenylphosphine(30.7 mg, 0.117 mmol) in THF (2 mL) at 80° C. using a syringe pump over4 h. The mixture was stirred at 80° C. for 1 h. Solvent was removed, theresidual was dissolved in 1 ml of DMF. The crude material was purifiedvia preparative LC/MS (method D, 65-85% B over 10 min., then an 8-minhold at 100% B). Fractions containing the desired product were combinedand dried via centrifugal evaporation to give Intermediate 54A (14.8 mg,0.028 mmol, 47.2% yield). ¹H NMR (500 MHz, methanol-d₄) δ 8.61 (s, 1H),8.18 (d, J=1.38 Hz, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.49-7.83 (m, 1H),7.42 (d, J=8.80 Hz, 1H), 7.11 (d, J=2.48 Hz, 1H), 6.92 (dd, J=2.48, 8.80Hz, 1H), 4.15 (t, J=5.50 Hz, 2H), 3.63 (t, J=5.23 Hz, 2H), 2.99 (s, 3H),2.61 (s, 3H), 1.45 (s, 9H). LC-MS: method C, RT=2.69 min, MS (ESI) m/z:500.2 (M+H)⁺.

Example 54

To a solution of Intermediate 54A (9 mg, 0.018 mmol) in DCM (1 mL) wasadded TFA (1 ml). The mixture was stirred at room temperature for 1h.Solvent was removed and the crude sample was purified with preparativeHPLC (method A, 30-100% B in 6 min.). The desired fractions were placedin a SpeedVac overnight to remove solvent, then lyophilized to giveExample 54 (7 mg, 0.013 mmol, 74.9% yield). ¹H NMR (400 MHz,methanol-d₄) δ 8.68 (s, 1H), 8.23 (d, J=1.77 Hz, 1H), 8.06 (s, 1H), 7.70(s, 1H), 7.56-7.97 (m, 1H), 7.52 (d, J=8.84 Hz, 1H), 7.29 (d, J=2.53 Hz,1H), 7.07 (dd, J=2.65, 8.97 Hz, 1H), 4.28-4.38 (m, 2H), 3.45-3.58 (m,2H), 2.83 (s, 3H), 2.64 (s, 3H). ¹⁹F NMR (376 MHz, methanol-d₃) δ −76.92(br. s., 3F), −95.23-88.19 (m, 2F). LC-MS: method C, RT=2.02 min, MS(ESI) m/z: 400.0 (M+H)⁺. Analytical HPLC purity (method A): 99%

Example 552-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-dimethoxybenzo[d]thiazole

Intermediate 55A: 2,7-dibromo-4,6-dimethoxybenzo[d]thiazole

To a mixture of 4,6-dimethoxybenzo[d]thiazol-2-amine (0.5 g, 2.378 mmol)and p-TSA monohydrate (1.357 g, 7.13 mmol) in acetonitrile (20 mL) at10° C. (cooled with ice water) was added dropwise a solution of sodiumnitrite (0.328 g, 4.76 mmol) and potassium bromide (0.707 g, 5.95 mmol)in water (5 mL) over a period of 25 min. The reaction mixture wasstirred at 10° C. for 10 min, and allowed to warm up to room temperatureand stirred for 1.0 h. The mixture was turned to a clear brown solution.To the reaction mixture was added sodium bicarbonate (pH to 9.0), waterand EtOAc. The organic layer was collected, washed with water, saturatedNa₂S₂O₃, water, brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 40 g ISCO column which was eluted with hexanes for 2min., then a 20 min gradient from 0% to 40% EtOAc in hexanes. Thedesired fraction was collected and concentrated to Intermediate 55A (110mg, 13% yield). ¹H NMR (400 MHz, chloroform-d) δ 6.60 (s, 1H), 4.06 (s,3H), 3.98 (s, 3H). LC-MS: method C, RT=2.18 min, MS (ESI) m/z: 351 353and 355 (M+H)⁺.

Intermediate 55B7-bromo-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,6-dimethoxybenzo[d]thiazole

To Intermediate 55A (26 mg, 0.074 mmol) and Intermediate I-1 (30 mg,0.088 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixturewas stirred at room temperature until solids are dissolved, then[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (4.81 mg, 5.89 μmol) was added. The flask wasdegassed and flushed with argon. Finally sodium carbonate (0.055 mL, 2M,0.110 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 100°C. for 2h. The reaction mixture was cooled to room temperature and wasdiluted with EtOAc and water, extracted with EtOAc (3×). The combinedorganic layer was washed with brine, dried with MgSO₄ and concentrated.The crude sample was purified with a preparative HPLC (method A, 70-100%B in 6 min.). The desired fractions were placed in a SpeedVac overnightto remove solvent, then lyophilized to give Intermediate 55B (8 mg,0.016 mmol, 22.07% yield). ¹H NMR (400 MHz, chloroform-d) δ 8.85 (d,J=1.77 Hz, 1H), 8.73 (s, 1H), 7.79 (dd, J=0.88, 1.90 Hz, 1H), 7.47-7.89(m, 1H), 6.68 (s, 1H), 4.15 (s, 3H), 4.04 (s, 3H), 2.67 (s, 3H). ¹⁹F NMR(400 MHz, chloroform-d) −90.12 (s, 2F). LC-MS: method C, RT=2.56 min, MS(ESI) m/z: 481.9 and 484.0 (M+H)⁺.

Example 55

To a solution of Intermediate 55B (6 mg, 0.012 mmol) in ethyl acetate (5ml) was added Pd/C (5 mg) and TEA (10.40 μl, 0.075 mmol) and the mixturewas stirred under a hydrogen balloon at 50° C. for 2 h. The reactionmixture was cooled to room temperature and filtered. The filtrate wasconcentrated. The crude material was purified via preparative LC/MS(method D, 45-90% B over 10 min., then a 10-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to Example 55 (0.2 mg, 0.496 μmol, 3.99% yield).¹H NMR (500 MHz, methanol-d₄) δ 8.76 (d, J=1.65 Hz, 1H), 8.67 (s, 1H),7.77 (d, J=0.83 Hz, 1H), 7.48-7.85 (m, 1H), 7.03 (s, 1H), 6.59 (d,J=2.20 Hz, 1H), 4.05 (s, 3H), 3.89 (s, 3H). LC-MS: method C, RT=2.46min, MS (ESI) m/z: 404 (M+H)⁺. Analytical HPLC purity (method A): 100%.

Example 56 2-methoxy-5-(5-methoxybenzofuran-2-yl)-7-methylquinoxaline

Intermediate 56A: 5-methoxybenzofuran-2-ylboronic acid

To 5-methoxybenzofuran (188 mg, 1.269 mmol) in THF (4.0 mL) at −78° C.was added 1.6 N n-BuLi in hexanes (1.190 mL, 1.903 mmol) dropwise. Thesolution turned to slightly yellow. The mixture was stirred at −78° C.for 20 min, followed by addition of triisopropyl borate (0.737 mL, 3.17mmol). The mixture was stirred for 30 min, and the cooling bath wasremoved to allow warm up to room temperature over 1.5 h. It was dilutedwith EtOAc, quenched with 3.0 mL of 1.0 N HCl. After stirring at roomtemperature for 25 min, the organic layer was collected, washed withbrine, dried over sodium sulfate. After evaporation of solvent, thecrude product was dissolved in a small amount of chloroform with a dropof MeOH, and charged to a 4 g silica gel cartridge which was eluted withhexanes for 2 min., then a 10 min gradient from 0% to 60% EtOAc inhexanes. The desired fractions were combined, concentrated andlyophilized to give Intermediate 56A (170 mg, 0.886 mmol, 69.8% yield)as a white solid. ¹H NMR (500 MHz, methanol-d₄) δ 7.41 (d, J=9.1 Hz,1H), 7.30 (s, 1H), 7.14 (d, J=2.5 Hz, 1H), 6.96 (dd, J=8.9, 2.6 Hz, 1H),3.84 (s, 3H); LC-MS: method A, RT=1.45 min, MS (ESI) m/z: 149.0(M-B(OH)₂)⁺.

Example 56

To Intermediate I-9A (20 mg, 0.079 mmol) and Intermediate 56A (20.48 mg,0.107 mmol) was added toluene (0.75 mL) and EtOH (0.250 mL). Thereaction mixture was stirred at room temperature until solids aredissolved, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (5.16 mg, 6.32 μmol) was added. The flask wasdegassed and flushed with argon. Finally sodium carbonate (0.079 mL, 2M,0.158 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 120°C. for 30 min. The reaction mixture was cooled to room temperature andwas diluted with EtOAc and water, extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude material was purified via preparative LC/MS(method D, 55-90% B over 10 min., then a 10-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to yield Example 56 (13.7 mg, 0.043 mmol, 54.1%yield). ¹H NMR (500 MHz, methanol-d₄) δ 8.47 (s, 1H), 8.06 (d, J=1.93Hz, 1H), 7.94 (d, J=0.83 Hz, 1H), 7.56-7.65 (m, 2H), 7.41 (d, J=9.08 Hz,1H), 7.11 (d, J=2.48 Hz, 1H), 6.90 (dd, J=2.48, 8.80 Hz, 1H), 4.09 (s,3H), 3.85 (s, 3H), 2.59 (s, 3H). LC-MS: method C, RT=2.63 min, MS (ESI)m/z: 321 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 582-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-methoxybenzo[d]thiazole

To Intermediate 15F (15 mg, 0.075 mmol) and Intermediate I-1 (30.3 mg,0.090 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixturewas stirred at room temperature until solids are dissolved, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (7.36 mg, 9.02 μmol) was added. The flask wasdegassed and flushed with argon. Finally sodium carbonate (0.056 mL, 2M,0.113 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 120°C. for 30 min. The reaction mixture was cooled to room temperature andwas diluted with EtOAc and water, extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude sample was purified with a preparative HPLC(method A, 65-100% B in 8 min.). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to give Example58 (10.5 mg, 0.028 mmol, 37.1% yield). ¹H NMR (400 MHz, chloroform-d) δ8.84 (d, J=1.52 Hz, 1H), 8.72 (s, 1H), 7.81-7.83 (m, 1H), 7.79 (dd,J=0.63, 8.21 Hz, 1H), 7.45-7.87 (m, 2H), 6.88 (d, J=7.83 Hz, 1H), 4.07(s, 3H), 2.70 (s, 3H). ¹⁹F NMR (400 MHz, chloroform-d) −90.12 (s, 2F).LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 374.0 (M+H)⁺. AnalyticalHPLC purity (method A): 99%.

Example 592-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluoro-6-methoxybenzo[d]thiazole

Intermediate 59A: 4-fluoro-6-methoxybenzo[d]thiazol-2-amine

To 2-fluoro-4-methoxyaniline (636 mg, 4.51 mmol) in acetonitrile (14 mL)was added ammonium thiocyanate (515 mg, 6.76 mmol). The mixture wasstirred at room temperature for 10 min. Then it was cooled with tapewater, and benzyltrimethylammonium tribromide (1757 mg, 4.51 mmol) inacetonitrile (5.0 mL) was added dropwise (10 min). The mixture was thenstirred at room temperature overnight. The mixture was diluted withEtOAc/saturated sodium bicarbonate. The organic layer was collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount ofchloroform/a small amount of MeOH and charged to a 40 g silica gelcartridge which was eluted with 5% EtOAc in hexanes for 3 min., then a12 min gradient from 5% to 75% EtOAc in hexanes. The desired fractionswere combined and concentrated to give Intermediate 59A (0.65 g, 3.28mmol, 72.8% yield) as a pale solid. ¹H NMR (500 MHz, DMSO-d₆) δ 6.84 (d,J=1.7 Hz, 1H), 6.75 (br. s., 2H), 6.55 (dd, J=12.1, 2.2 Hz, 1H),3.74-3.72 (m, 3H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ −124.96 (s, 1F); LC-MS:method A, RT=1.17 min, MS (ESI) m/z: 199.0 (M+H).

Intermediate 59B: 2-bromo-4-fluoro-6-methoxybenzo[d]thiazole

To a suspension of Intermediate 59A (0.32 g, 1.614 mmol) in acetonitrile(15 mL) was added p-TSA monohydrate (0.983 g, 5.17 mmol). The saltformed was stirred at room temperature for 15 min, and at 10° C. (cooledwith ice water) for 5 min, followed by dropwise addition of a solutionof sodium nitrite (0.223 g, 3.23 mmol) and potassium bromide (0.480 g,4.04 mmol) in water (5 mL) over a period of 2 min. The reaction mixturewas stirred at from 10° C. to room temperature overnight. The reactionwas quenched with saturated sodium bicarbonate. The insoluble materialwas removed by filtration. The filtrate was extracted with EtOAc. Theorganic layer was washed with brine, dried over sodium sulfate. Afterevaporation of solvent, the crude product was dissolved in a smallamount of chloroform and charged to a 12 g silica gel cartridge whichwas eluted with hexanes for 2 min., then a 15 min gradient from 0% to30% EtOAc in hexanes. The desired fractions were combined andconcentrated to give Intermediate 59B (0.15 g, 0.572 mmol, 35.5% yield)as a pale yellow solid. ¹H NMR (500 MHz, chloroform-d) δ 7.07 (dd,J=2.2, 0.8 Hz, 1H), 6.84 (dd, J=11.6, 2.2 Hz, 1H), 3.89 (s, 3H); ¹⁹F NMR(471 MHz, chloroform-d) δ −119.63 (s, 1F); LC-MS: method A, RT=1.87 min,MS (ESI) m/z: 262.0 and 264.0 (M+H)⁺.

Example 59

To Intermediate 59B (15 mg, 0.057 mmol) and Intermediate I-1 (23.08 mg,0.069 mmol) was added toluene (0.75 mL) and EtOH (0.25 mL). The mixturewas stirred at room temperature until solids are dissolved, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (5.61 mg, 6.87 μmol) was added. The flask wasdegassed and flushed with argon. Finally sodium carbonate (0.043 mL, 2M,0.086 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 120°C. for 40 min. The reaction mixture was cooled to room temperature andwas diluted with EtOAc and water, extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude sample was purified with a preparative HPLC(method A, 60-100% B in 8 min.). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to give Example59 (8.5 mg, 0.022 mmol, 37.9% yield). ¹H NMR (400 MHz, chloroform-d) δ8.86 (d, J=1.52 Hz, 1H), 8.70 (s, 1H), 7.81 (d, J=0.76 Hz, 1H),7.45-7.97 (m, 1H), 7.22 (d, J=2.27 Hz, 1H), 6.88 (dd, J=2.15, 11.75 Hz,1H), 3.92 (s, 3H), 2.69 (s, 3H). ¹⁹F NMR (376 MHz, chloroform-d) δ−90.22 (s, 2F), −121.48 (br. s., 1F). LC-MS: method C, RT=2.53 min, MS(ESI) m/z: 391.9 (M+H)⁺. Analytical HPLC purity (method A): 100%.

Example 602-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazole

To 2-chloro-5-fluorobenzo[d]thiazole (15 mg, 0.080 mmol) andIntermediate I-1 (32.2 mg, 0.096 mmol) was added toluene (0.75 mL) andEtOH (0.25 mL). The mixture was stirred at room temperature until solidsare dissolved, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (7.83 mg, 9.59 μmol) was added. The flask wasdegassed and flushed with Ar. Finally sodium carbonate (2M, 0.12 mL,0.24 mmol) was added dropwise. The reaction vessel was sealed andbubbled with argon for 5 min, then placed in microwave reactor at 120°C. for 40 min. The reaction mixture was cooled to room temperature andwas diluted with EtOAc and water, extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude material was purified via preparative LC/MS(method D, 60-100% B over 10 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to yield Example 60 (18.8 mg, 0.052 mmol, 65.1%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.75 (d, J=1.65 Hz,1H), 8.15 (dd, J=4.81, 8.94 Hz, 1H), 8.09 (dd, J=2.48, 8.53 Hz, 1H),7.93 (s, 1H), 7.73-8.04 (m, 1H), 7.44 (dt, J=2.75, 9.08 Hz, 1H), 2.67(s, 3H). LC-MS: method C, a=2.54 min, MS (ESI) m/z: 361.9 (M+H)⁺.Analytical HPLC purity (method A): 100%.

Example 61 Methyl2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole-7-carboxylate

Intermediate 61A: methyl 2-bromobenzo[d]thiazole-7-carboxylate

tert-Butyl nitrite (1.111 mL, 8.40 mmol) was added to copper (II)bromide (1.770 g, 7.92 mmol) in dry acetonitrile (15 mL) under argon.The mixture was stirred at room temperature for 10 min. A suspension ofmethyl 2-aminobenzo[d]thiazole-7-carboxylate (1.0 g, 4.80 mmol) in dryacetonitrile (15 mL) was added dropwise. The reaction mixture wasstirred at room temperature for 1.5 h. The mixture was heated at 50° C.for 45 min. Acetonitrile was removed under vacuum, the reaction mixturewas diluted with EtOAc, quenched with 1.0 N HCl. The organic layer wascollected, washed with 0.5 N HCl (2×), saturated sodium bicarbonate,brine, dried over sodium sulfate. After evaporation of solvent,Intermediate 61A (1.2 g, 4.41 mmol, 92% yield) was obtained as brownsolid. It was used for next step without further purification. ¹H NMR(500 MHz, chloroform-d) δ 8.19 (dd, J=8.0, 1.1 Hz, 1H), 8.13 (dd, J=7.7,1.1 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 4.05 (s, 3H); LC-MS: method A,RT=2.02 min, MS (ESI) m/z: 272.0 274.0 (M+H)⁺.

Example 61

To Intermediate I-1 (30 mg, 0.089 mmol), Intermediate 61A (31.6 mg,0.116 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.83 mg, 7.14 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (0.098 mL,2M, 0.196 mmol). The reaction mixture was heated in a microwave reactorat 120° C. for 30 min. To the reaction mixture was added EtOAc/water.The organic layers were collected, dried over sodium sulfate. Afterevaporation of solvent, the crude product was purified via preparativeLC/MS (method D, 55-95% B over 10 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to yield Example 61 (2.9 mg, 7.08 μmol, 7.93%).¹H NMR (500 MHz, Methanol-d₄) δ 8.73 (s, 1H), 8.71 (d, J=1.65 Hz, 1H),8.30 (dd, J=0.83, 7.98 Hz, 1H), 8.15 (dd, J=0.83, 7.43 Hz, 1H), 7.84 (s,1H), 7.61 (t, J=7.70 Hz, 1H), 7.52-7.82 (m, 1H), 4.05 (s, 3H), 2.68 (s,3H). LC-MS: method C, RT=2.41 min, MS (ESI) m/z: 402.10 (M+H)⁺.Analytical HPLC purity (method B): 98%

Example 62 Methyl2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

Intermediate 62A2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

To Example 11 (19 mg, 0.042 mmol) was added 4.0 N HCl in dioxane (1059μl, 4.24 mmol). The mixture was aged at room temperature for 2.0 h.Solvent was removed and the product was lyophilized overnight to giveIntermediate 62A (14 mg, 0.034 mmol, 81% yield). ¹H NMR (500 MHz,methanol-d₄) δ 8.65 (s, 1H), 8.61 (s, 1H), 7.82 (s, 1H), 7.65 (t,J_(HF)=71.53 Hz, 1H), 4.56 (br. s., 2H), 3.77-3.73 (m, 2H), 3.72-3.68(m, 2H), 2.66 (s, 3H); ¹⁹F NMR (471 MHz, methanol-d₄) δ −90.23 (s, 2F);LC-MS: method A, RT=1.70 min, MS (ESI) m/z: 349.0 (M+H)⁺.

Example 62

To a solution of Intermediate 62A (9 mg, 0.026 mmol) and DIEA (0.023 mL,0.129 mmol) in DCM (1 mL) was added a solution of methyl chloroformate(4.00 μl, 0.052 mmol) in DCM (1 mL). The mixture was stirred at roomtemperature for 1.0 h. The reaction mixture was diluted with EtOAc andwater, extracted with EtOAc. The combined organic layer was washed withbrine, dried with MgSO₄ and concentrated. The crude was purified with apreparative HPLC (method A, 60-100% B in 6 min.). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto give Example 62 (8 mg, 0.018 mmol, 68.6% yield). ¹H NMR (400 MHz,chloroform-d) δ 8.63 (s, 1H), 8.55 (s, 1H), 7.74 (s, 1H), 7.40-7.97 (m,1H), 4.82 (br. s., 2H), 3.88 (br. s., 2H), 3.79 (s, 3H), 3.05 (br. s.,2H), 2.64 (s, 3H). ¹⁹F NMR (376 MHz, chloroform-d) δ −90.20 (s, 2F).LC-MS: method C, RT=2.43 min, MS (ESI) m/z: 406.9 (M+H)⁺. AnalyticalHPLC purity (method A): 92%.

Example 63N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

To a solution of Intermediate I-4 (12 mg, 0.027 mmol) and DIEA (23.88μl, 0.137 mmol) in DCM (2 ml) was added a solution of benzenesulfonylchloride (9.66 mg, 0.055 mmol) in 0.2 ml of DCM. The mixture was stirredat room temperature for 1 h. The reaction mixture was diluted with EtOAcand water, extracted with EtOAc. The combined organic layer was washedwith brine, dried with MgSO₄ and concentrated. The crude sample waspurified with a preparative HPLC (method A, 50-100% B in 6 min.). Thedesired fractions were placed in a SpeedVac overnight to remove solvent,then lyophilized to give Example 63 (10 mg, 0.018 mmol, 64.7% yield). ¹HNMR (400 MHz, acetonitrile-d₃) δ 8.90-8.58 (m, 2H), 7.95 (d, J=8.8 Hz,1H), 7.90-7.50 (m, 7H), 7.05 (dd, J=8.8, 2.5 Hz, 1H), 5.97 (br. s., 1H),4.06 (t, J=5.3 Hz, 2H), 3.33 (q, J=5.6 Hz, 2H), 2.68 (s, 3H). ¹⁹F NMR(376 MHz, acetonitrile-d₃) δ −90.50 (s, 2F). LC-MS: method C, RT=2.39min, MS (ESI) m/z: 543.0 (M+H)⁺. Analytical HPLC purity (method A): 96%.

Example 64(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methanol

Intermediate 64A: (2-bromobenzo[d]thiazol-7-yl)methanol

To a solution of Intermediate 61A (0.53 g, 1.948 mmol) in THF (10 mL) at0° C. was added 1.0 M Super-H in THF (4.28 mL, 4.28 mmol) dropwise. Themixture was stirred at 0° C. for 1.0 h. The reaction mixture was dilutedwith EtOAc, quenched with saturated ammonium chloride at 0° C., and thenwith a few drops of 1.0 N HCl. The organic layer was washed with brine,dried over sodium sulfate. After evaporation of solvent, the crudeproduct was dissolved in a small amount of chloroform and was purifiedwith 40 g ISCO column eluted with hexanes for 3 min, then an 18 mingradient from 0 to 100% EtOAc in hexanes. The desired fractions werecombined and concentrated to give Intermediate 64A (380 mg, 1.557 mmol,80% yield) as a light yellow solid. ¹H NMR (400 MHz, Methanol-d₄) δ 7.80(d, J=8.08 Hz, 1H), 7.44 (t, J=7.71 Hz, 1H), 7.31 (d, J=7.33 Hz, 1H),4.83 (s, 2H). LC-MS: method C, RT=1.58 min, MS (ESI) m/z: 243 and 245(M+H)⁺.

Example 64

To Intermediate I-1 (106 mg, 0.315 mmol), Intermediate 64A (100 mg,0.410 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20.59 mg, 0.025 mmol) was addedtoluene (7.5 mL) and EtOH (2.500 mL). The mixture was sonicated for 1min, and flushed with argon. To this was added sodium carbonate (0.315mL, 2M, 0.630 mmol). The reaction mixture was heated in a microwavereactor at 120° C. for 30 min. The reaction mixture was diluted withEtOAc and water, extracted with EtOAc (3×). The combined organic layerwas washed with brine, dried with MgSO₄ and concentrated. The crudesample was purified 12 g ISCO column eluted with 0-100% EtOAc in hexanesfor 15 min., followed by a preparative HPLC (method A, 30-100% B in 8min.). The desired fractions were placed in a SpeedVac overnight toremove solvent, then lyophilized to give Example 64 (88 mg, 0.261 mmol,83% yield). ¹H NMR (500 MHz, methanol-d₄) δ 8.76 (s, 1H), 8.02 (d,J=8.25 Hz, 1H), 7.88 (dd, J=1.10, 1.93 Hz, 1H), 7.62-7.94 (m, 1H),7.50-7.58 (m, 1H), 7.43 (dd, J=0.96, 7.29 Hz, 1H), 4.94 (s, 2H), 2.69(s, 3H). ¹⁹F NMR (376 MHz, methanol-d₄) δ −91.06 (s, 2F). LC-MS: methodC, RT=2.24 min, MS (ESI) m/z: 373.9 (M+H)⁺. Analytical HPLC purity(method A): 98%.

Example 652-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(methoxymethyl)benzo[d]thiazole

To a suspension of Example 64 (18 mg, 0.048 mmol) in THF (1 mL) wasadded NaH (3.86 mg, 0.096 mmol) and the mixture was stirred at roomtemperature for 30 min Then Met (0.090 mL, 1.446 mmol) was added. Themixture was heated up to 50° C. for 2 h. The mixture was diluted withEtOAc and water, extracted with EtOAc. The combined organic layer waswashed with brine, dried with MgSO₄ and concentrated. The crude waspurified with a preparative HPLC (method A, 50-100% B in 6 min.). Thedesired fractions were placed in a SpeedVac overnight to remove solvent,then lyophilized to give Example 65 (2 mg, 5.06 μmol, 10.49% yield). ¹HNMR (400 MHz, chloroform-d) δ 8.82 (d, J=2.02 Hz, 1H), 8.75 (s, 1H),8.13 (d, J=8.08 Hz, 1H), 7.84 (s, 1H), 7.48-7.88 (m, 2H), 7.39 (d,J=7.33 Hz, 1H), 4.84 (s, 2H), 3.49 (s, 3H), 2.70 (s, 3H). ¹⁹F NMR (376MHz, chloroform-d) δ −90.20 (s, 2F). LC-MS: method C, RT=2.45 min, MS(ESI) m/z: 387.9 (M+H)⁺. Analytical HPLC purity (method A): 99%.

Example 66N-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methyl)benzenesulfonamide

Intermediate 66A: tert-butylN-[(2-bromo-1,3-benzothiazol-7-yl)methyl]-N-[(tert-butoxy)carbonyl]carbamate

A solution of DIAD (0.134 mL, 0.688 mmol) in THF (2 mL) was added to asolution of di-tert-butyl iminodicarboxylate (150 mg, 0.688 mmol),Intermediate 64A (56 mg, 0.229 mmol) and triphenylphosphine (181 mg,0.688 mmol) in THF (2 mL). The mixture was stirred at room temperaturefor 1 h, diluted with DCM and saturated NaHCO₃, extracted with DCM, thecombined organic layer was washed with brine, dried MgSO₄ andconcentrated. The crude sample was purified with 40 g ISCO column elutedwith 0-100% DCM/Hex for 20 min, the desired fraction was collected togive Intermediate 66A (55 mg, 0.124 mmol, 54.1% yield) as a yellowsolid. ¹H NMR (500 MHz, chloroform-d) δ 7.90 (d, J=7.98 Hz, 1H), 7.45(t, J=7.84 Hz, 1H), 7.30 (dd, J=0.83, 7.43 Hz, 1H), 4.98 (s, 2H),1.41-1.46 (m, 18H). LC-MS: method C, RT=2.37 min, MS (ESI) m/z: 908.9[2M+23]⁺.

Intermediate 66B: tert-butylN-[(tert-butoxy)carbonyl]-N-({2-[2-(difluoromethoxy)-7-methylquinoxalin-5-yl]-1,3-benzothiazol-7-yl}methyl)carbamate

To Intermediate I-1 (37.9 mg, 0.113 mmol), Intermediate 66A (50 mg,0.113 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (7.37 mg, 9.02 μmol) was addedtoluene (7.5 mL) and EtOH (2.500 mL). The mixture was sonicated for 1min, and flushed with argon. To this was added sodium carbonate (0.113mL, 2M, 0.226 mmol). The reaction mixture was heated in a microwavereactor at 120° C. for 30 min. The reaction mixture was diluted withEtOAc and water, extracted with EtOAc. The combined organic layer waswashed with brine, dried with MgSO₄ and concentrated. The crude samplewas purified with a preparative HPLC (method A, 70-100% B in 6 min.).The desired fractions were placed in a SpeedVac overnight to removesolvent, then lyophilized to give Intermediate 66B (21 mg, 0.035 mmol,30.9% yield). ¹H NMR (500 MHz, methanol-d₄) δ 8.76 (s, 1H), 8.02 (d,J=8.25 Hz, 1H), 7.88 (dd, J=1.10, 1.93 Hz, 1H), 7.62-7.94 (m, 1H),7.50-7.58 (m, 1H), 7.43 (dd, J=0.96, 7.29 Hz, 1H), 4.94 (s, 2H), 2.69(s, 3H). ¹⁹F NMR (376 MHz, methanol-d) δ −90.20 (s, 2F). LC-MS: methodC, RT=2.62 min, MS (ESI) m/z: 573.2 (M+H)⁺.

Intermediate 66C: tert-butyl(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methylcarbamate

To a solution of Intermediate 66B (17 mg, 0.030 mmol) in DCM (1 mL) wasadded TFA (0.023 mL, 0.297 mmol). The mixture was stirred at roomtemperature for 15 min, diluted with EtOAc and water, extracted withEtOAc. The combined organic layer was washed with NaHCO₃ and brine,dried with MgSO₄ and concentrated. The crude sample was purified with apreparative HPLC (method A, 70-100% B in 6 min.). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto give Intermediate 66C (13 mg, 0.027 mmol, 92% yield). ¹H NMR (400MHz, chloroform-d) δ 8.83 (d, J=1.8 Hz, 1H), 8.70 (s, 1H), 8.10 (d,J=7.8 Hz, 1H), 7.84 (d, J=1.0 Hz, 1H), 7.87-7.48 (m, 3H), 7.37 (d, J=6.8Hz, 1H), 2.70 (s, 3H), 1.52 (s, 9H). ¹⁹F NMR (376 MHz, chloroform-d) δ−90.20 (s, 2F). LC-MS: method C, RT=2.44 min, MS (ESI) m/z: 472.9(M+H)⁺.

Intermediate 66D(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)methanamine

To a solution of Intermediate 66C (11 mg, 0.022 mmol, 94% yield) in DCMwas added TFA (359 μl, 4.66 mmol) and the mixture was stirred at roomtemperature for 15 min. The crude was purified with a preparative HPLC(method A, 30-100% B in 6 min.). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to giveIntermediate 66D (11 mg, 0.022 mmol, 94% yield). ¹H NMR (400 MHz,methanol-d₄) δ 8.80 (d, J=1.8 Hz, 1H), 8.71 (s, 1H), 8.16 (d, J=8.1 Hz,1H), 7.92-7.59 (m, 3H), 7.52-7.44 (m, 1H), 4.44 (s, 2H), 2.70 (s, 3H).¹⁹F NMR (376 MHz, methanol-d₄) δ −78.07 (s, 3F), −92.13 (s, 2F). LC-MS:method C, RT=1.91 min, MS (ESI) m/z: 372.9 (M+H)⁺.

Example 66

To a solution of Intermediate 66D (8 mg, 0.016 mmol) and DIEA (0.014 mL,0.082 mmol) in DCM (1 mL) was added a solution of benzenesulfonylchloride (5.81 mg, 0.033 mmol) in 0.2 ml of DCM. The mixture was stirredat room temperature for 1.0 h. Solvent was removed, the residual waspurified with a preparative HPLC (method A, 50-100% B in 6 min.). Thedesired fractions were placed in a SpeedVac overnight to remove solvent,then lyophilized to give Example 66 (3 mg, 5.21 μmol, 31.7% yield). ¹HNMR (400 MHz, chloroform-d) δ 8.76 (d, J=1.8 Hz, 1H), 8.73 (s, 1H), 8.06(d, J=8.1 Hz, 1H), 7.92-7.84 (m, 3H), 7.70-7.30 (m, 6H), 4.93 (d, J=5.8Hz, 1H), 4.56 (d, J=5.8 Hz, 2H), 2.70 (s, 3H). ¹⁹F NMR (376 MHz,chloroform-d) δ −90.22 (s, 2F). LC-MS: method C, RT=2.30 min, MS (ESI)m/z: 513.1 (M+H)⁺. Analytical HPLC purity (method A): 90%

Example 67N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

Intermediate 67A: 2-bromo-4-fluorobenzo[d]thiazol-6-ol

Aluminum chloride (308 mg, 2.308 mmol) was added to a solution ofIntermediate 59B (220 mg, 0.839 mmol) in toluene (4 mL). The mixture washeated at 85° C. for 1.5 h. The reaction mixture was cooled to roomtemperature, quenched with ice-cold 1.0 N HCl (10 mL) and EtOAc (10 mL),and stirred at room temperature for 30 min. The organic layer wascollected, washed with water, saturated sodium bicarbonate, brine, driedover sodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 12 g silicagel cartridge which was eluted with hexanes for 5 min., then an 18 mingradient from 0% to 40% EtOAc in hexanes. The desired fractions werecombined and concentrated to give Intermediate 67A (45 mg, 0.181 mmol,21.61% yield) as brown solid. ¹H NMR (400 MHz, methanol-d₄) δ 6.98 (dd,J=2.3, 0.8 Hz, 1H), 6.71 (dd, J=11.9, 2.3 Hz, 1H). LC-MS: method C,RT=1.72 min, MS (ESI) m/z: 247 and 249 (M+H)⁺.

Intermediate 67B: tert-butyl2-(2-bromo-4-fluorobenzo[d]thiazol-6-yloxy)ethylcarbamate

A solution of DIAD (0.088 mL, 0.453 mmol) and tert-butyl(2-hydroxyethyl) carbamate (0.070 mL, 0.453 mmol) in THF (1 mL) wasadded to a solution of Intermediate 67A (45 mg, 0.181 mmol) andtriphenylphosphine (71.4 mg, 0.272 mmol) in THF (2 mL) at 80° C. usingsyringe pump over 2 h. The mixture was concentrated and redissolved in 1ml of DCM and was purified with a 12 g ISCO column eluted with 0-70%EtOAc in hexanes for 15 min, the desired fraction was collected to giveIntermediate 67B (30 mg, 0.077 mmol, 42.3% yield). ¹H NMR (400 MHz,chloroform-d) δ 7.05 (d, J=1.8 Hz, 1H), 6.82 (dd, J=11.4, 2.3 Hz, 1H),5.13-4.95 (m, 1H), 4.07 (t, J=5.1 Hz, 2H), 3.62-3.48 (m, 2H), 1.48-1.42(m, 9H). LC-MS: method C, RT=2.14 min, MS (ESI) m/z: 391 and 393 (M+H)⁺.

Intermediate 67C: tert-butyl2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazol-6-yloxy)ethylcarbamate

To Intermediate I-1 (23 mg, 0.068 mmol), Intermediate 67B (29.4 mg,0.075 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (4.47 mg, 5.47 μmol) was addedtoluene (0.75 mL) and EtOH (0.250 mL). The mixture was sonicated for 1min, and flushed with argon. To this was added sodium carbonate (0.068mL, 2M, 0.137 mmol). The reaction mixture was heated in a microwavereactor at 100° C. for 30 min. To the reaction mixture was addedEtOAc/water. The organic layers were collected, dried over sodiumsulfate. The crude residue was purified with a 12 g ISCO column elutedwith 0-70% EtOAc in hexanes for 15 min. The desired fraction wasconcentrated and further purified with a preparative HPLC (method A,70-100% B in 6 min.). The desired fractions were placed in a SpeedVacovernight to remove solvent, then lyophilized to give Intermediate 67C(30 mg, 0.054 mmol, 79% yield). ¹H NMR (400 MHz, chloroform-d) δ 8.85(d, J=1.8 Hz, 1H), 8.69 (s, 1H), 7.81 (dd, J=1.9, 0.9 Hz, 1H), 7.95-7.41(m, 1H), 7.21 (d, J=2.0 Hz, 1H), 6.88 (dd, J=11.6, 2.3 Hz, 1H), 4.13 (t,J=5.1 Hz, 2H), 3.60 (br. s., 2H), 2.69 (s, 3H), 1.48 (s, 9H). ¹⁹F NMR(376 MHz, chloroform-d) δ −90.55 (s, 2F), −123.30 (br. s., 1F). LC-MS:method C, RT=2.47 min, MS (ESI) m/z: 521.2 (M+H)⁺.

Intermediate 67D2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-fluorobenzo[d]thiazol-6-yloxy)ethanamine

To a solution of Intermediate 67C (25 mg, 0.048 mmol) in DCM (1 mL) wasadded TFA (0.920 mL, 11.94 mmol). The mixture was stirred at roomtemperature for 1 h. Solvent was removed, the residual was purified witha preparative HPLC (method A, 30-100% B in 6 min.). The desiredfractions were placed in a SpeedVac overnight to remove solvent, thenlyophilized to give Intermediate 67D (22 mg, 0.040 mmol, 84% yield). ¹HNMR (400 MHz, methanol-d₄) δ 8.78 (d, J=2.0 Hz, 1H), 8.74 (s, 1H), 7.87(d, J=1.0 Hz, 1H), 8.00-7.55 (m, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.04 (dd,J=11.9, 2.3 Hz, 1H), 4.43-4.30 (m, 2H), 3.52-3.41 (m, 2H), 2.69 (s, 3H).¹⁹F NMR (376 MHz, methanol-d₄) δ −77.57 (br. s., 3F), −84.34-98.20 (s2F), −123.30 (br. s., 1F). LC-MS: method C, RT=2.03 min, MS (ESI) m/z:421.2 (M+H)⁺.

Example 67

To a solution of Intermediate 67D (15 mg, 0.028 mmol) and DIEA (49.0 μl,0.281 mmol) in DCM was added a solution of benzenesulfonyl chloride(7.20 μl, 0.056 mmol) in 0.2 ml of DCM. The mixture was stirred at roomtemperature for 1.0 h. The reaction mixture was diluted with EtOAc andwater, extracted with EtOAc. The combined organic layer was washed withbrine, dried with MgSO₄ and concentrated. The crude sample was purifiedwith a preparative HPLC (method A, 50-100% B in 6 min.). The desiredfractions were placed in a SpeedVac overnight to remove solvent, thenlyophilized to give Example 67 (4 mg, 6.64 μmol, 23.64% yield). ¹H NMR(400 MHz, chloroform-d) δ 8.86 (d, J=1.8 Hz, 1H), 8.69 (s, 1H),7.98-7.90 (m, 2H), 7.81 (s, 1H), 7.64-7.50 (m, 3H), 7.87-7.43 (m, 1H),7.10 (d, J=2.3 Hz, 1H), 6.77 (dd, J=11.5, 2.1 Hz, 1H), 4.96 (t, J=5.9Hz, 1H), 4.10 (t, J=5.1 Hz, 2H), 3.47 (q, J=5.3 Hz, 2H), 2.69 (s, 3H).¹⁹F NMR (376 MHz, chloroform-d) δ −90.22 (s, 2F), −120.80 (br. s., 1F).LC-MS: method C, RT=2.40 min, MS (ESI) m/z: 560.9 (M+H)⁺. AnalyticalHPLC purity (method A): 95%.

Example 682-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazole

To Intermediate I-1 (20 mg, 0.059 mmol),2-chloro-5-methylbenzo[d]thiazole (14.21 mg, 0.077 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (3.89 mg, 4.76 μmol) was added toluene (1.5mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min, and flushedwith argon. To this was added sodium carbonate (0.065 mL, 2M, 0.131mmol). The reaction mixture was heated in a microwave reactor at 100° C.for 30 min. To the reaction mixture was added EtOAc/water. The organiclayers were collected, dried over sodium sulfate. After evaporation ofsolvent, the crude was purified with a preparative HPLC (method A,50-100% B in 6 min.). The desired fractions were placed in a SpeedVacovernight to remove solvent, then lyophilized to give Example 68 (11 mg,0.030 mmol, 50.7% yield). ¹H NMR (400 MHz, chloroform-d) δ 8.81 (d,J=2.0 Hz, 1H), 8.71 (s, 1H), 7.97 (s, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.82(dd, J=1.9, 0.9 Hz, 1H), 7.85-7.48 (m, 1H), 7.28 (br. s., 1H), 2.70 (s,3H), 2.56 (s, 3H). ¹⁹F NMR (376 MHz, chloroform-d) δ −90.20 (s, 2F).LC-MS: method C, RT=2.57 min, MS (ESI) m/z: 357.9 (M+H)⁺. AnalyticalHPLC purity (method A): 98%.

Example 69 Methyl2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethylcarbamate

Intermediate 69A: 2-chlorobenzo[d]thiazol-7-ol

Aluminum chloride (184 mg, 1.377 mmol) was added to a solution of2-chloro-7-methoxybenzo[d]thiazole (100 mg, 0.501 mmol) in toluene (2mL). The mixture was heated at 85° C. for 1.5 h. HPLC indicated acomplete conversion of starting material. The reaction mixture wascooled to room temperature, quenched with ice-cold 1.0 N HCl (50 mL) andEtOAc (50 mL), and stirred at room temperature for 30 min. The organiclayer was collected, washed with water, saturated sodium bicarbonate,brine, dried over sodium sulfate. After evaporation of solvent, thecrude product was dissolved in a small amount of chloroform and chargedto a 12 g silica gel cartridge which was eluted with hexanes for 5 min.,then a 10 min gradient from 0% to 40% EtOAc in hexanes. The desiredfractions were combined and concentrated to give Intermediate 69A (85mg, 0.458 mmol, 91% yield) as brown solid. ¹H NMR (400 MHz, methanol-d₄)δ 7.47-7.36 (m, 1H), 7.35-7.24 (m, 1H), 6.82 (d, J=8.1 Hz, 1H). LC-MS:method C, RT=1.72 min, MS (ESI) m/z: 185.8 (M+H)⁺.

Intermediate 69B: tert-butyl2-(2-chlorobenzo[d]thiazol-7-yloxy)ethylcarbamate

A solution of DIAD (0.223 mL, 1.145 mmol) and tert-butyl(2-hydroxyethyl) carbamate (0.177 mL, 1.145 mmol) in THF (1 mL) wasadded to a solution of Intermediate 69A (85 mg, 0.458 mmol) andtriphenylphosphine (180 mg, 0.687 mmol) in THF (2 mL) at 80° C. usingsyringe pump over 3 h. LCMS indicated a completion of the reaction. Themixture was diluted with EtOAc and saturated NaHCO₃, extracted withEtOAc, the combined organic layer was washed with brine, dried withMgSO₄ and concentrated. The crude was purified with a 12 g ISCO columneluted with 0-70% EtOAc in hexanes for 15 min, the desired fraction wascollected to give Intermediate 69B (125 mg, 0.380 mmol, 83% yield). ¹HNMR (400 MHz, chloroform-d) δ 7.58 (dd, J=8.2, 0.6 Hz, 1H), 7.41 (t,J=8.1 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 4.21 (t, J=5.2 Hz, 2H), 3.60 (q,J=5.3 Hz, 2H), 1.51-1.44 (m, 9H). LC-MS: method C, RT=2.17 min, MS (ESI)m/z: 329. (M+H)⁺.

Intermediate 69C: tert-butyl2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethylcarbamate

To Intermediate I-1 (29 mg, 0.086 mmol), Intermediate 69B (32.6 mg,0.099 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.64 mg, 6.90 μmol) was addedtoluene (0.75 mL) and EtOH (0.250 mL). The mixture was sonicated for 1min, and flushed with argon. To this was added sodium carbonate (0.086mL, 2M, 0.173 mmol). The reaction mixture was heated in a microwavereactor at 100° C. for 30 min. To the reaction was added EtOAc/water,extracted with EtOAc. The combined organic layer was washed with brine,dried with MgSO₄ and concentrated. The crude sample was purified with a12 g ISCO column eluted with 0-50% EtOAc in hexane for 15 min. Thedesired fraction was collected and concentrated to give Intermediate 69C(35 mg, 0.068 mmol, 79% yield). ¹H NMR (400 MHz, acetonitrile-d₃) δ 8.79(s, 1H), 8.77 (d, J=1.8 Hz, 1H), 7.80 (dd, J=1.9, 0.9 Hz, 1H), 7.67-7.62(m, 1H), 7.97-7.56 (m, 1H), 7.41 (t, J=8.1 Hz, 1H), 6.96 (d, J=8.1 Hz,1H), 4.25 (t, J=5.7 Hz, 2H), 3.53 (q, J=5.8 Hz, 2H), 2.66 (d, J=13.6 Hz,1H), 2.63 (s, 3H), 1.33 (s, 9H). ¹⁹F NMR (376 MHz, acetonitrile-d₃) δ−90.55 (s, 2F). LC-MS: method C, RT=2.49 min, MS (ESI) m/z: 503.0(M+H)⁺.

Intermediate 69D2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethanamine

To a solution of Intermediate 69C (30 mg, 0.060 mmol) in DCM (1 mL) wasadded TFA (0.920 mL, 11.94 mmol). The mixture was stirred at roomtemperature for 1 h. Solvent was removed, the residual was purified witha preparative HPLC (method A, 30-100% B in 6 min.). The desiredfractions were placed in a SpeedVac overnight to remove solvent, thenlyophilized to give Intermediate 69D (30 mg, 0.058 mmol, 96% yield). ¹HNMR (400 MHz, methanol-d₄) δ 8.79 (d, J=1.8 Hz, 1H), 8.73 (s, 1H), 7.90(d, J=0.8 Hz, 1H), 7.79 (s, 1H), 7.99-7.60 (m, 1H), 7.53 (t, J=8.1 Hz,1H), 7.06 (d, J=8.1 Hz, 1H), 4.56-4.42 (m, 2H), 3.52 (t, J=4.9 Hz, 2H),2.70 (s, 3H). ¹⁹F NMR (376 MHz, methanol-d₄) δ −77.64 (br. s., 3F),−91.57 (br. s., 2F). LC-MS: method C, RT=1.96 min, MS (ESI) m/z: 402.9(M+H)⁺.

Example 69

To a solution of Intermediate 69D (10 mg, 0.019 mmol) and DIEA (0.017mL, 0.097 mmol) in DCM (1 mL) was added a solution of methylchloroformate (3.00 μl, 0.039 mmol) in DCM. The mixture was stirred atroom temperature for 1 hour. The reaction mixture was diluted with EtOAcand water, and then extracted with EtOAc. The combined organic layer waswashed with brine, dried with MgSO₄ and concentrated. The crude samplewas purified with a preparative HPLC (method A, 60-100% B in 6 min.).The desired fractions were placed in a SpeedVac overnight to removesolvent, then lyophilized to give Example 69 (5.5 mg, 0.011 mmol, 58.6%yield). ¹H NMR (400 MHz, acetonitrile-d₃) δ 8.84-8.81 (m, 1H), 8.79 (s,1H), 7.90-7.46 (m, 5H), 6.99 (d, J=7.8 Hz, 1H), 4.29 (t, J=5.4 Hz, 2H),3.65-3.56 (m, 6H), 2.70 (s, 3H). ¹⁹F NMR (376 MHz, acetonitrile-d₃) δ−86.49-95.62 (m, 2F). LC-MS: method C, RT=2.36 min, MS (ESI) m/z: 461.0(M+H)⁺. Analytical HPLC purity (method A): 95%.

Example 70 Methyl2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-7-yloxy)ethylcarbamate

Intermediate 70A: 2-chloro-7-methoxy-4-methylbenzo[d]thiazole

To a solution of copper (II) chloride (1.030 g, 7.66 mmol) inacetonitrile (60 mL) at 40° C. was added tert-butyl nitrite (1.097 mL,8.30 mmol), followed by Intermediate 12C (1.24 g, 6.38 mmol) as a solid.The mixture was stirred at 40° C. for 1.0 h, diluted with EtOAc, washedwith 1.0 N HCl, water and brine. After evaporation of solvent, the crudeproduct was dissolved in a small amount of chloroform and charged to a40 g silica gel cartridge which was eluted with 5% dichloromethane inhexanes for 2 min., then a 12 min gradient from 5% to 50%dichloromethane in hexanes. The desired fractions were combined andconcentrated to give Intermediate 70A (1.2 g, 5.62 mmol, 88% yield) as aslightly yellow solid.

Intermediate 70B: 2-chloro-4-methylbenzo[d]thiazol-7-ol

Aluminum chloride (369 mg, 2.77 mmol) was added to a solution ofIntermediate 70A (215 mg, 1.006 mmol) in toluene (4 mL). The mixture washeated at 85° C. for 1.5 h. The reaction mixture was cooled to roomtemperature, quenched with ice-cold 1.0 N HCl (50 mL) and EtOAc (50 mL),and stirred at room temperature for 30 min. The organic layer wascollected, washed with water, saturated sodium bicarbonate, brine, driedover sodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 40 g silicagel cartridge which was eluted with hexanes for 5 min., then an 18 mingradient from 0% to 40% EtOAc in hexanes. The desired fractions werecombined and concentrated to give Intermediate 70B (105 mg, 0.526 mmol,52.3% yield) as brown solid. ¹H NMR (400 MHz, Methanol-d₄) δ 6.98 (dd,J=2.3, 0.8 Hz, 1H), 6.71 (dd, J=11.9, 2.3 Hz, 1H). LC-MS: method C,RT=2.20 min, MS (ESI) m/z: 547.2 (M+H)⁺. LC-MS: method C, RT=1.87 min,MS (ESI) m/z: 199.8 (M+H)⁺.

Intermediate 70C: tert-butyl2-(2-chloro-4-methylbenzo[d]thiazol-7-yloxy) ethylcarbamate

A solution of DIAD (0.243 mL, 1.252 mmol) and Intermediate 70B (100 mg,0.501 mmol) in THF (1 mL) was added to a solution of tert-butyl(2-hydroxyethyl) carbamate (0.194 mL, 1.252 mmol) and triphenylphosphine(197 mg, 0.751 mmol) in THF (2 mL) at 80° C. using a syringe pump for 2h. The mixture was diluted with dichloromethane and saturated NaHCO₃,extracted with dichloromethane, the combined organic layer was washedwith brine, dried with MgSO₄ and concentrated. The crude sample waspurified with 40 g ISCO column eluted with 0-100% EtOAc in hexanes for20 min, the desired fraction was collected to give Intermediate 70C (170mg, 0.496 mmol, 99% yield) as a yellow solid. ¹H NMR (400 MHz,chloroform-d) δ 7.17 (dd, J=8.2, 0.9 Hz, 1H), 6.74 (d, J=8.3 Hz, 1H),5.09-4.94 (m, 1H), 4.23-4.14 (m, 2H), 3.57 (q, J=5.1 Hz, 2H), 2.60 (d,J=0.5 Hz, 3H), 1.55-1.42 (m, 9H). LC-MS: method C, RT=2.26 min, MS (ESI)m/z: 342.9 (M+H)⁺.

Intermediate 70D: tert-butyl2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-7-yloxy)ethylcarbamate

To Intermediate I-1 (33.9 mg, 0.101 mmol), Intermediate 70C (45 mg,0.131 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (6.60 mg, 8.08 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (0.111 mL,2M, 0.222 mmol). The reaction mixture was heated in a microwave reactorat 100° C. for 30 min. To the reaction mixture was added EtOAc/water.The organic layers were collected, dried over sodium sulfate. Afterevaporation of solvent, the crude product was purified with a 12 g ISCOcolumn eluted with 0-70% EtOAc in hexanes for 15 min. The desiredfraction was collected to give Intermediate 70D (46 mg, 0.087 mmol, 86%yield) was obtained as a yellow solid. ¹H NMR (400 MHz, chloroform-d) δ8.87 (d, J=1.5 Hz, 1H), 8.74 (s, 1H), 7.81 (dd, 1.0 Hz, 1H), 7.94-7.46(m, 1H), 7.23 (dd, J=8.0, 0.9 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 4.25 (t,J=4.9 Hz, 2H), 3.67 (d, J=4.8 Hz, 2H), 2.81 (s, 3H), 2.71 (s, 3H), 1.48(s, 9H). ¹⁹F NMR (376 MHz, chloroform-d) δ −90.17 (s, 2F). LC-MS: methodC, RT=2.63 min, MS (ESI) m/z: 517.0 (M+H)⁺.

Intermediate 70E2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-7-yloxy)ethanamine

To a solution of Intermediate 70D (40 mg, 0.077 mmol) in DCM (1 mL) wasadded TFA (0.597 mL, 7.74 mmol). The mixture was stirred at roomtemperature for 1 h. Solvent was removed, the residual was purified witha preparative HPLC (method A, 30-100% B in 6 min.). The desiredfractions were placed in a SpeedVac overnight to remove solvent, thenlyophilized to Intermediate 70E (35 mg, 0.065 mmol, 84% yield). ¹H NMR(400 MHz, Methanol-d₄) δ 8.85 (s, 1H), 8.71 (s, 1H), 7.87 (s, 1H),8.01-7.54 (m, 1H), 7.29 (d, J=8.1 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 4.45(t, J=4.9 Hz, 2H), 3.48 (t, J=4.9 Hz, 2H), 2.78 (s, 3H), 2.71 (s, 3H).¹⁹F NMR (376 MHz, Methanol-d₄) δ −78.76 (br. s., 3F), −92.71 (s, 2F).LC-MS: method C, RT=2.10 min, MS (ESI) m/z: 416.9 (M+H)⁺.

Example 70

To a solution of Intermediate 70E (10 mg, 0.019 mmol) and DIEA (0.016mL, 0.094 mmol) in DCM (1 mL) was added a solution of methylchloroformate (2.92 μl, 0.038 mmol) in DCM. The mixture was stirred atroom temperature for 1 h. The reaction mixture was diluted with EtOAcand water, extracted with EtOAc. The combined organic layer was washedwith brine, dried with MgSO₄ and concentrated. The crude was purifiedwith a preparative HPLC (method A, 60-100% B in 6 min.). The desiredfractions were placed in a SpeedVac overnight to remove solvent, thenlyophilized to give Example 70 (5.5 mg, 0.019 mmol, 59% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.80 (d, J=1.8 Hz, 1H), 7.93 (s, 1H),8.11-7.68 (m, 1H), 7.42 (br. s., 1H), 7.30 (d, J=7.8 Hz, 1H), 6.98 (d,J=8.1 Hz, 1H), 4.22 (t, J=5.6 Hz, 2H), 3.50-3.38 (m, 5H), 2.71 (s, 3H),2.69 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −88.27 (s, 2F). LC-MS: methodC, RT=2.49 min, MS (ESI) m/z: 475.0 (M+H)⁺. Analytical HPLC purity(method A): 96%.

Example 712-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-(thiazol-4-ylmethoxy)benzo[d]thiazole

Intermediate 71A: 2-chlorobenzo[d]thiazol-6-ol

Aluminum chloride (6.01 g, 45.1 mmol) was added to a solution of2-chloro-6-methoxybenzo[d]thiazole (3 g, 15.03 mmol) in toluene (80 mL).The mixture was heated at 110° C. for 1.5 h. TLC indicated a completeconversion of starting material. The reaction mixture was cooled to roomtemperature, quenched with ice-cold 1.0 N HCl (50 mL), stirred at roomtemperature for 30 min. The precipitate was collected by filtration,washed with water (3×), saturated sodium bicarbonate (3×), water (3×)and air-dried for 1.0 h under vacuum. It was further dried under highvacuum overnight to give Intermediate 71A (2.6 g, 14.01 mmol, 93% yield)as a pale gray solid. The crude sample was used for the next stepwithout further purification. ¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (d,J=8.8 Hz, 1H), 7.25 (s, 1H), 7.00 (dd, J=8.8, 1.5 Hz, 1H). LC-MS: methodC, RT=1.65 min, MS (ESI) m/z: 185.8 (M+H)⁺.

Intermediate 71B:6-(tert-butyldimethylsilyloxy)-2-chlorobenzo[d]thiazole

To a stirred solution of Intermediate 71A (2.6 g, 14.01 mmol) in DMF (50mL) was added TBDMS-Cl (2.96 g, 19.61 mmol) and imidazole (1.669 g,24.51 mmol). The reaction mixture was left stirring at room temperaturefor 1.0 h. The mixture was diluted with EtOAc/water and extracted withEtOAc. The combined organic layer was washed with brine, dried oversodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 120 g ISCOcolumn which was eluted with hexanes for 3 min., then a 30 min gradientfrom 0% to 50% EtOAc in hexanes. The desired fractions were combined andconcentrated to give Intermediate 71B (3 g, 10.00 mmol, 71.4% yield) asclear orange oil. ¹H NMR (400 MHz, chloroform-d) δ 7.80 (s, 1H), 7.21(s, 1H), 7.03-6.94 (m, 1H), 1.01 (s, 9H), 0.24 (s, 6H). LC-MS: method C,RT=2.57 min, MS (ESI) m/z: 300 (M+H)⁺.

Intermediate 71C6-(tert-butyldimethylsilyloxy)-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazole

To Intermediate I-1 (1 g, 3.94 mmol), Intermediate 71B (1.358 g, 4.53mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex with dichloromethane (1:1) (0.161 g, 0.197 mmol) was addedtoluene (9 mL), EtOH (3 mL) and sodium carbonate (3.94 mL, 2 M, 7.87mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 135° C. for 30 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layers were collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount oftoluene/chloroform and charged to a 120 g silica gel cartridge which waseluted with hexanes for 3 min., then a 20 min gradient from 0% to 75%dichloromethane in hexanes (flow rate 65 mL/min). The desired fractionswere combined and concentrated to give Intermediate 71C (1.6 g, 2.70mmol, 68.6% yield) as a bright yellow solid. ¹H NMR (400 MHz,chloroform-d) δ 8.75 (d, J=1.8 Hz, 1H), 8.69 (s, 1H), 8.03-7.98 (m, 1H),7.81-7.78 (m, 1H), 7.86-7.49 (m, 1H), 7.40 (d, J=2.5 Hz, 1H), 7.06 (dd,J=8.7, 2.4 Hz, 1H), 2.69 (s, 3H), 1.04 (s, 9H), 0.27 (s, 6H). LC-MS:method C, gradient time 1 min, RT=2.30 min, MS (ESI) m/z: 473.9 (M+H)⁺.

Intermediate 71D:2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-ol

To a solution of Intermediate 71C (1.75 g, 3.70 mmol) in THF (15 mL) atroom temperature was added acetic acid (0.465 mL, 8.13 mmol), followedby addition of 1.0 N TBAF in THF (4.43 mL, 4.43 mmol) dropwise. Themixture was stirred at room temperature for 20 min. The mixture wasdiluted with EtOAc, washed with water, saturated sodium bicarbonate(2×), brine, and dried over sodium sulfate. After evaporation of thesolvent, the crude product was triturated with EtOAc in hexanes (1:4).The precipitate was collected by filtration to give Intermediate 71D (1g, 2.78 mmol, 75% yield) as a yellow solid. ¹H NMR (400 MHz,Methanol-d₄) δ 8.70 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 7.96 (s, 1H),7.93-7.53 (m, 3H), 7.34 (d, J=2.3 Hz, 1H), 7.03 (dd, J=8.8, 2.5 Hz, 1H),2.67 (s, 3H). LC-MS: method C, gradient time 1 min, RT=1.45 min, MS(ESI) m/z: 359.9 (M+H)⁺.

Example 71

A solution of DIAD (0.019 mL, 0.100 mmol) in toluene (0.5 mL) was addedto a mixture of Intermediate 71D (12 mg, 0.033 mmol),thiazol-4-ylmethanol (11.54 mg, 0.100 mmol) and triphenylphosphine(17.52 mg, 0.067 mmol) in toluene (2 mL) at 110° C. on 5 portions (0.4ml each for 30 min). The mixture turned to a clear solution and wasstirred at 110° C. for 30 min. The mixture was concentrated and purifiedwith a preparative HPLC (method A, 70-100% B in 6 min.). The desiredfractions were placed in a SpeedVac overnight to remove solvent, thenlyophilized to give Example 71 (5 mg, 9.86 μmol, 29.5% yield). ¹H NMR(400 MHz, acetonitrile-d₃) δ 8.95 (d, J=2.0 Hz, 1H), 8.78-8.73 (m, 2H),7.99 (d, J=8.8 Hz, 1H), 7.81 (dd, J=1.9, 0.9 Hz, 1H), 7.71 (d, J=2.5 Hz,1H), 7.63 (d, J=2.0 Hz, 1H), 7.89-7.48 (m, 1H), 7.24 (dd, J=9.1, 2.5 Hz,1H), 5.35 (s, 2H), 2.68 (s, 3H). NMR (376 MHz, acetonitrile-d₃) δ −90.50(s, 2F). LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 456.9 (M+H)⁺.Analytical HPLC purity (method A): 90%.

Example 72N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

To a solution of Example 63 (6.9 mg, 0.013 mmol) in THF (0.5 mL) wasadded sodium methoxide (0.076 mL, 0.038 mmol). The mixture was stirredat room temperature for 1 h. The reaction mixture was diluted with EtOAcand water, extracted with EtOAc. The combined organic layer was washedwith brine, dried with MgSO₄ and concentrated. The crude sample waspurified with a preparative HPLC (method A, 60-100% B in 6 min.). Thedesired fractions were placed in a SpeedVac overnight to remove solvent,then lyophilized to give Example 72 (4 mg, 7.11 μmol, 55.9% yield). ¹HNMR (400 MHz, chloroform-d) δ 8.61 (d, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.02(d, J=8.8 Hz, 1H), 7.95-7.89 (m, 2H), 7.78 (dd, J=1.9, 0.9 Hz, 1H),7.61-7.56 (m, 1H), 7.55-7.49 (m, 2H), 7.30 (d, J=2.5 Hz, 1H), 7.03 (dd,J=8.8, 2.5 Hz, 1H), 5.00 (t, J=5.9 Hz, 1H), 4.14 (s, 3H), 4.10 (t, J=5.1Hz, 2H), 3.47 (q, J=5.7 Hz, 2H), 2.66 (s, 3H). LC-MS: method C, RT=2.37min, MS (ESI) m/z: 507.0 (M+H)⁺. Analytical HPLC purity (method A): 95%.

Example 73N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

To a solution of Intermediate 26F (28 mg, 0.054 mmol) in DCM (1 mL) wasadded DIEA (0.095 ml, 0.542 mmol) and benzenesulfonyl chloride (19.15mg, 0.108 mmol). The mixture was stirred at room temperature for 1 hour.Solvent was removed under vacuum and the residual was purified with apreparative HPLC (method A, 70-100% B in 6 min.). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto Example 73 (15 mg, 0.025 mmol, 46.2% yield). ¹H NMR (400 MHz,chloroform-d) δ 8.74 (d, J=1.8 Hz, 1H), 8.68 (s, 1H), 8.00-7.89 (m, 2H),7.87-7.44 (m, 5H), 7.15 (d, J=2.3 Hz, 1H), 6.93-6.85 (m, 1H), 4.10 (t,J=5.1 Hz, 2H), 3.46 (t, J=5.1 Hz, 2H), 2.82 (s, 3H), 2.70 (s, 3H). ¹⁹FNMR (376 MHz, chloroform-d) δ −90.22 (s, 2F). LC-MS: method C, RT=2.46min, MS (ESI) m/z: 557.0 (M+H)⁺. Analytical HPLC purity (method A): 96%.

Example 742-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)ethanol

A solution of DIAD (0.041 mL, 0.209 mmol) in toluene (0.5 mL) was addedto a mixture of Intermediate 15J (25 mg, 0.070 mmol),2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol (20.34 mg, 0.139 mmol) andtriphenylphosphine (36.5 mg, 0.139 mmol) in toluene (2 mL) at 110° C. on5 portion of 0.4 ml each for 30 min. The mixture turned to a cleansolution and was stirred at 110° C. for 30 min. The mixture wasconcentrated and the residual was dissolved in 1 ml of DCM and treatedwith 12N HCl (0.290 mL, 3.48 mmol) and the mixture was stirred at roomtemperature for 1 h. The mixture was concentrated and purified with apreparative HPLC (method A, 50-100% B in 6 min.). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto give Example 74 (11.5 mg, 0.027 mmol, 38.5% yield). ¹H NMR (400 MHz,acetonitrile-d₃) δ 8.81 (d, J=2.0 Hz, 1H), 8.78 (s, 1H), 7.84 (dd,J=1.9, 0.9 Hz, 1H), 7.90-7.46 (m, 3H), 6.99 (d, J=7.8 Hz, 1H), 4.33-4.25(m, 2H), 3.99-3.92 (m, 2H), 2.69 (s, 3H). ¹⁹F NMR (376 MHz,acetonitrile-d₃) δ −90.50 (s, 2F). LC-MS: method C, RT=2.33 min, MS(ESI) m/z: 403.9 (M+H)⁺. Analytical HPLC purity (method A): 94%

Example 752-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d]thiazole

A solution of DIAD (0.016 mL, 0.083 mmol) in toluene (0.5 mL) was addedto a mixture of Intermediate 15J (10 mg, 0.028 mmol), 2-methoxyethanol(4.24 mg, 0.056 mmol) and triphenylphosphine (14.60 mg, 0.056 mmol) intoluene (2 mL) at 110° C. on 5 portion of 0.4 ml each for 30 min. Themixture turned to a clean solution and was stirred at 110° C. for 30min. The mixture was concentrated and redissolved in 1 ml of DMF and waspurified with a preparative HPLC (method A, 60-100% B in 6 min.). Thedesired fractions were placed in a SpeedVac overnight to remove solvent,then lyophilized to give Example 75 (10 mg, 0.023 mmol, 82% yield). ¹HNMR (400 MHz, acetonitrile-d₃) δ 8.81 (d, J=2.0 Hz, 1H), 8.79 (s, 1H),7.84 (d, J=0.8 Hz, 1H), 7.90-7.43 (m, 3H), 6.99 (d, J=7.8 Hz, 1H),4.44-4.25 (m, 2H), 3.87-3.80 (m, 2H), 3.44 (s, 3H), 2.69 (s, 3H)¹⁹F NMR(376 MHz, acetonitrile-d₃) δ −90.22 (s, 2F). LC-MS: method C, RT=2.46min, MS (ESI) m/z: 418.0 (M+H)⁺. Analytical HPLC purity (method A): 99%.

Example 76 benzyl2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-ylcarbamate

To a solution of Intermediate 21A (15 mg, 0.042 mmol) in DCM (1 mL) wasadded DIEA (0.044 mL, 0.251 mmol). After stirring at room temperaturefor 2 min, benzyl carbonochloridate (0.013 mL, 0.092 mmol) was added.The mixture was heated up to 60° C. for 2 h. The mixture wasconcentrated and redissolved in 1 ml of DMF and was purified with apreparative HPLC (method A, 50-100% B in 6 min.). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto give Example 76 (5 mg, 9.95 μmol, 23.77% yield). ¹H NMR (400 MHz,acetonitrile-d₃) δ 8.80 (d, J=1.8 Hz, 1H), 8.73 (s, 1H), 7.89 (dd,J=8.1, 0.8 Hz, 1H), 7.83 (s, 1H), 7.75 (br. s., 1H), 7.60 (d, J=7.8 Hz,1H), 7.86-7.51 (m, 1H), 7.48-7.44 (m, 2H), 7.43-7.33 (m, 3H), 5.25 (s,2H), 2.68 (s, 3H). ¹⁹F NMR (376 MHz, acetonitrile-d₃) δ −90.22 (s, 2F).LC-MS: method C, RT=2.41 min, MS (ESI) m/z: 492.9 (M+H)⁺. AnalyticalHPLC purity (method A): 98%.

Example 772-(2-methoxy-7-methylquinoxalin-5-yl)-6-(2-methoxyethoxy)benzo[d]thiazole

Intermediate 77A2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-(2-methoxyethoxy)benzo[d]thiazole

A solution of DIAD (0.016 mL, 0.083 mmol) in toluene (0.5 mL) was addedto a mixture of Intermediate 71D (10 mg, 0.028 mmol), 2-methoxyethanol(4.24 mg, 0.056 mmol) and triphenylphosphine (14.60 mg, 0.056 mmol) intoluene (2 mL) at 110° C. on 5 portion of 0.4 ml each for 30 min andthen was stirred at 110° C. for 30 min. The mixture was concentrated andredissolved in 1 ml of DMF and was purified with a preparative HPLC(method A, 60-100% B in 6 min.). The desired fractions were placed in aSpeedVac overnight to remove solvent, then lyophilized to giveIntermediate 77A (10 mg, 0.023 mmol, 82% yield). ¹H NMR (400 MHz,acetonitrile-d₃) δ 8.75 (d, J=1.8 Hz, 1H), 8.74 (s, 1H), 7.98 (d, J=8.8Hz, 1H), 7.81 (dd, J=1.9, 0.9 Hz, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.88-7.50(m, 1H), 7.16 (dd, J=8.8, 2.5 Hz, 1H), 4.27-4.08 (m, 2H), 3.82-3.67 (m,2H), 3.40 (s, 3H), 2.68 (s, 3H). ¹⁹F NMR (376 MHz, acetonitrile-d₃) δ−90.22 (s, 2F). LC-MS: method C, RT=2.47 min, MS (ESI) m/z: 418.1(M+H)⁺. Analytical HPLC purity (method A): 95%.

Example 77

To a solution of Intermediate 77A (5 mg, 0.012 mmol) in THF (0.5 mL) wasadded sodium methoxide (0.072 mL, 0.036 mmol). The mixture was stirredat room temperature for 1 h. The reaction was quenched by 1 drop ofwater and concentrated. The residual was purified via preparative LC/MS(method C, 50-90% B over 10 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to Example 77 (3.0 mg, 7.79 μmol, 65.0% yield).¹H NMR (500 MHz, methanol-d₄) δ 8.51 (s, 1H), 8.47 (d, J=1.9 Hz, 1H),7.95 (d, J=9.1 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.47 (s, 1H), 7.15 (dd,J=8.8, 2.5 Hz, 1H), 4.24-4.18 (m, 2H), 4.11 (s, 3H), 3.85-3.78 (m, 2H),2.63 (s, 3H). LC-MS: method C, RT=2.41 min, MS (ESI) m/z: 382.15 (M+H)⁺.Analytical HPLC purity (method B): 99%.

Example 782-(2-methoxy-7-methylquinoxalin-5-yl)-7-(2-methoxyethoxy)benzo[d]thiazole

To a solution of Example 75 (8.5 mg, 0.020 mmol) in THF (0.5 mL) wasadded sodium methoxide (0.122 mL, 0.061 mmol). The mixture was stirredat room temperature for 1 h. The reaction was quenched by 1 drop ofwater solvent was removed, the residual was purified via preparativeLC/MS (method C, 50-90% B over 10 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to Example 78 (6.6 mg, 0.017 mmol, 85% yield).¹H NMR (500 MHz, methanol-d₄) δ 8.55 (s, 1H), 8.53 (d, J=1.9 Hz, 1H),7.76 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.1 Hz, 1H), 6.90 (d,J=7.7 Hz, 1H), 4.41-4.32 (m, 2H), 4.11 (s, 3H), 3.88 (dd, J=5.4, 3.7 Hz,2H), 3.50 (s, 3H), 2.63 (s, 3H). LC-MS: method C, RT=2.41 min, MS (ESI)m/z: 382.15 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 79N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

Intermediate 79AN-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-2,2,2-trifluoro-N-(phenylsulfonyl)acetamide

To a solution of Intermediate 26F (28 mg, 0.054 mmol) in DCM (1 ml) wasadded TFA (0.418 ml, 5.42 mmol) and the mixture was stirred at roomtemperature for 1 hour. Solvent was removed and the sample was undervacuum overnight. The residual was dissolved in DCM (1 ml) then DIEA(0.095 ml, 0.542 mmol) and benzenesulfonyl chloride (19.15 mg, 0.108mmol) was added. The mixture was stirred at room temperature for 1 hour.Solvent was removed under vacuum and the residual was purified with apreparative HPLC (method A, 70-100% B in 6 min.). The desired fractionswere placed in a SpeedVac overnight to remove solvent, then lyophilizedto give Intermediate 79A (8 mg, 0.012 mmol, 22.62% yield). LC-MS: methodC, RT=2.68 min, MS (ESI) m/z: 653 (M+H)⁺.

Example 79

To a solution of Intermediate 79A (8 mg, 0.012 mmol) in THF (0.5 mL) wasadded sodium methoxide (0.074 mL, 0.037 mmol). The mixture was stirredat room temperature for 1 h. The reaction was quenched by 1 drop ofwater and concentrated. The residual was diluted with 1 ml of DMF andwas purified via preparative LC/MS (method C, 55-90% B over 20 min.,then a 10-min hold at 90% B). Fractions containing the desired productwere combined and dried via centrifugal evaporation to Example 79 (3.9mg, 7.49 μmol, 61.1% yield). ¹H NMR (500 MHz, methanol-d₄) δ 8.55 (d,J=1.7 Hz, 1H), 8.51 (s, 1H), 7.88 (s, 1H), 7.87-7.85 (m, 1H), 7.73 (s,1H), 7.54 (d, J=7.2 Hz, 1H), 7.51-7.46 (m, 2H), 7.13 (d, J=2.2 Hz, 1H),6.80 (d, J=1.7 Hz, 1H), 4.10 (s, 3H), 4.03 (t, J=5.5 Hz, 2H), 3.34 (t,J=5.5 Hz, 2H), 2.75 (s, 3H), 2.64 (s, 3H). LC-MS: method C, RT=2.48 min,MS (ESI) m/z: 521.0 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 80 Methyl2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-ylcarbamate

To a solution of Intermediate 21A (6 mg, 0.017 mmol) in DCM (1 mL) wasadded DIEA (0.058 mL, 0.335 mmol). After stirring at room temperaturefor 2 min, methyl chloroformate (18.99 mg, 0.201 mmol) was added to thesolution and the mixture was stirred at 60° C. for 3h. Solvent wasremoved, the residual was dissolved in 1 ml of DMF and purified viapreparative LC/MS (method C, 35-70% B over 10 min., then a 5-min hold at100% B). Fractions containing the desired product were combined anddried via centrifugal evaporation to afford Example 80 (3.6 mg, 8.30μmol, 49.6% yield). ¹H NMR (500 MHz, methanol-d₄) δ 8.72-8.68 (m, 2H),7.88 (d, J=8.8 Hz, 1H), 7.84-7.52 (m, 3H), 7.51-7.45 (m, 1H), 3.82 (s,3H), 2.67 (s, 3H). LC-MS: method C, RT=2.24 min, MS (ESI) m/z: 416.9(M+H)⁺. Analytical HPLC purity (method B): 96%

Example 81N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide

To a solution of Intermediate 26F (10 mg, 0.022 mmol) and DIEA (0.039mL, 0.221 mmol) in DCM (1 mL) was added a solution of4-fluorobenzene-1-sulfonyl chloride (8.59 mg, 0.044 mmol) in 0.2 ml ofDCM. The mixture was stirred at room temperature for 1 h. Solvent wasremoved under vacuum and the residual was purified via preparative LC/MS(method C, 45-85% B over 10 min., then a 7-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to Example 81 (4.4 mg, 7.66 μmol, 34.7% yield).¹H NMR (500 MHz, methanol-d₄) δ 8.71 (d, J=1.9 Hz, 1H), 8.67 (s, 1H),7.93-7.88 (m, 2H), 7.78 (dd, 1.0 Hz, 1H), 7.83-7.51 (m, 1H), 7.23-7.12(m, 3H), 6.80 (dd, J=2.5, 0.8 Hz, 1H), 4.05 (t, J=5.5 Hz, 2H), 3.35 (t,J=5.5 Hz, 2H), 2.76 (s, 3H), 2.67 (s, 3H). LC-MS: method C, RT=2.50 min,MS (ESI) m/z: 575.1 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 822-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)-N-phenylacetamide

Intermediate 82A: tert-butyl2-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yl)oxy)acetate

To a solution of Intermediate 15J (20 mg, 0.056 mmol) in DMF (1 mL) wasadded butyl 2-bromoacetate (0.041 mL, 0.278 mmol) and NaH (4.45 mg,0.111 mmol). The mixture was stirred at room temperature for 30 min,diluted with EtOAc and water, extracted with EtOAc. The combined organiclayer was washed with brine, dried with MgSO₄ and concentrated. Thecrude sample was purified with a 12 g ISCO column eluted with 0-50%EtOAc in hexanes for 15 min. The desired fraction was collected to giveIntermediate 82A (25 mg, 0.053 mmol, 95% yield) as a yellow solid. ¹HNMR (500 MHz, Methanol-d₄) δ 8.71 (s, 2H), 7.87-7.66 (m, 3H), 7.44 (t,J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 4.78 (s, 2H), 2.68 (s, 3H), 1.48(s, 9H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z: 474 (M+H)⁺.

Intermediate 82B2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-7-yloxy)aceticacid

To a solution of Intermediate 82A (16 mg, 0.034 mmol) in DCM (1 mL) wasadded TFA (0.260 mL, 3.38 mmol). The mixture was stirred at roomtemperature overnight, Solvent was removed, the residual was dissolvedin 1 ml of DMF and was purified via preparative LC/MS (method D: 10-45%B over 10 min., then a 5-min hold at 100% B). Fractions containing thedesired product were combined and dried via centrifugal evaporation togive Intermediate 82B (14 mg, 0.034 mmol, 99% yield). LC-MS: method C,RT=2.25 min, MS (ESI) m/z: 418(M+H)⁺.

Example 82

To a solution of Intermediate 82B (6.5 mg, 0.016 mmol) in CH₂Cl₂ (1 mL)was added DIEA (27.2 μL, 0.156 mmol) and 1-propanephosphonic acid cyclicanhydride, (T₃P) (180 μL, 50 wt % solution in ethyl acetate, 0.047 mmol)was added aniline (5.80, 0.062 mmol). The reaction mixture was stirredat room temperature for 2h. Solvent was removed, the residual wasdissolved in 1 ml of DMF and was purified via preparative LC/MS (methodC, 50-90% B over 10 min., then a 7-min hold at 100% B). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford Example 82 (5.0 mg, 10.15 μmol, 65.2% yield). ¹HNMR (500 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.23 (s, 1H), 7.99 (d, J=1.7 Hz,1H), 7.36-6.91 (m, 2H), 6.82 (d, J=7.7 Hz, 2H), 6.71 (t, J=8.0 Hz, 1H),6.52 (t, J=8.0 Hz, 2H), 6.27 (s, 1H), 6.20 (d, J=7.7 Hz, 1H), 1.87 (s,3H), 1.73-1.57 (m, 3H). LC-MS: method C, RT=2.46 min, MS (ESI) m/z:493.1 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 83N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-(trifluoromethyl)benzenesulfonamide

To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058mL, 0.331 mmol) in DCM (1 mL) was added a solution of4-(trifluoromethyl)benzene-1-sulfonyl chloride (12.15 mg, 0.050 mmol) in0.2 ml of DCM. The mixture was stirred at room temperature for 1 h.Solvent was removed, the residual was purified via preparative LC/MS(method C, 55-95% B over 10 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to give Example 83 (6.2 mg, 9.93 μmol, 30.0%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.97-7.84 (m, 1H),7.51-7.41 (m, 1H), 7.26-7.22 (m, 2H), 7.17-7.12 (m, 2H), 7.21-6.91 (m,2H), 6.69-6.46 (m, 1H), 6.02-5.83 (m, 1H), 3.26-3.18 (m, 2H), 2.50 (s,2H), 1.89 (s, 3H), 1.86 (s, 3H). LC-MS: method C, RT=2.54 min, MS (ESI)m/z: 625.1 (M+H)⁺. Analytical HPLC purity (method B): 99%.

Example 84N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-2,4-difluorobenzenesulfonamide

To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058mL, 0.331 mmol) in DMF (1 mL) was added a solution of2,4-difluorobenzene-1-sulfonyl chloride (10.56 mg, 0.050 mmol) in 0.2 mlof DCM. The mixture was stirred at room temperature for 1 h. Solvent wasremoved, the residual was purified via preparative LC/MS (method C:0-100% B over 10 min., then a 5-min hold at 100% B). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give Example 84 (7.8 mg, 0.013 mmol, 39.7% yield). ¹H NMR(500 MHz, Methanol-d₄) δ 8.72 (s, 1H), 8.69 (s, 1H), 7.92 (d, J=6.1 Hz,1H), 7.79 (s, 1H), 7.84-7.52 (m, 1H), 7.15 (s, 1H), 7.01 (s, 1H),6.96-6.88 (m, 1H), 6.75 (s, 1H), 4.07-4.03 (m, 2H), 3.73 (s, 3H), 3.46(t, J=5.4 Hz, 2H). LC-MS: method C, RT=2.45 min, MS (ESI) m/z: 593.1(M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 85N-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-3,4-difluorobenzenesulfonamide

To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058mL, 0.331 mmol) in DMF (1 mL) was added a solution of3,4-difluorobenzene-1-sulfonyl chloride (10.56 mg, 0.050 mmol) in 0.2 mlof DCM. The mixture was stirred at room temperature for 2 h. Solvent wasremoved, the residual was purified via preparative LC/MS (method C:0-100% B over 10 min., then a 5-min hold at 100% B). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give Example 85 (2.3 mg, 3.88 μmol, 11.72% yield). ¹H NMR(500 MHz, Methanol-d₄) δ 8.75-8.71 (m, 1H), 8.69-8.66 (m, 1H), 7.85-7.51(m, 4H), 7.35-7.26 (m, 1H), 7.20-7.14 (m, 1H), 6.82-6.77 (m, 1H), 4.07(t, J=5.4 Hz, 2H), 3.38 (t, J=5.5 Hz, 2H), 2.77 (s, 3H), 2.68 (s, 3H).LC-MS: method C, RT=2.51 min, MS (ESI) m/z: 593.1 (M+H)⁺. AnalyticalHPLC purity (method B): 99%.

Example 86 4-chloro N (2 (2 (2(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058mL, 0.331 mmol) in DMF (1 mL) was added a solution of4-chlorobenzene-1-sulfonyl chloride (10.49 mg, 0.050 mmol) in 0.2 ml ofDCM. The mixture was stirred at room temperature for 1 h. LCMS indicateda completion of the reaction. Solvent was removed and the sample waspurified via preparative LC/MS (method C, 60-100% B over 10 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to Example 86 (4.9 mg,8.29 μmol, 25.03% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 1H),8.82-8.64 (m, 1H), 8.08-7.61 (m, 7H), 7.48-7.37 (m, 1H), 6.84-6.78 (m,1H), 4.09-4.00 (m, 2H), 3.25-3.22 (m, 2H), 2.73 (s, 3H), 2.68 (s, 3H).LC-MS: method C, RT=2.53 min, MS (ESI) m/z: 591.1 (M+H)⁺. AnalyticalHPLC purity (method B): 100%.

Example 87N-(2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-methylbenzenesulfonamide

Intermediate 87AN-(2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-methylbenzenesulfonamide

To a solution of Intermediate 26F (15 mg, 0.033 mmol) and DIEA (0.058mL, 0.331 mmol) in DMF (1 mL) was added a solution of4-methylbenzene-1-sulfonyl chloride (9.47 mg, 0.050 mmol) in 0.2 ml ofDCM. The mixture was stirred at room temperature for 1 h. LCMS indicateda completion of the reaction. Solvent was removed, the residual waspurified via preparative LC/MS (method C, 55-95% B over 10 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Intermediate 87A(5.5 mg, 9.64 μmol, 29% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s,1H), 8.72 (d, J=1.7 Hz, 1H), 8.04-7.74 (m, 2H), 7.72 (d, J=8.3 Hz, 2H),7.44 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 6.88 (d, J=1.4 Hz, 1H),4.04 (t, J=5.4 Hz, 2H), 3.17 (t, J=5.4 Hz, 2H), 2.73 (s, 3H), 2.67 (s,3H), 2.36 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 571.2(M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 87

To a solution of Intermediate 87A (3.32 mg, 5.82 μmol) in DMF (0.5 mL)was added sodium methoxide in MeOH (0.035 mL, 0.5M, 0.017 mmol). Themixture was stirred at room temperature for 2 h. LCMS indicatedcompletion of the reaction. The reaction was quenched by water and waspurified via preparative LC/MS (method C, 55-95% B over 10 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 87 (2.7mg, 5.05 μmol, 87% yield). ¹H NMR (500 MHz, Methanol-d₄) δ 8.55 (d,J=1.9 Hz, 1H), 8.51 (s, 1H), 7.74 (d, J=8.3 Hz, 3H), 7.27 (d, J=8.3 Hz,2H), 7.10 (d, J=2.5 Hz, 1H), 6.79 (d, J=1.4 Hz, 1H), 4.22 (br. s., 2H),4.10 (s, 3H), 4.01 (t, J=5.5 Hz, 2H), 3.35-3.33 (m, 2H), 2.75 (s, 3H),2.64 (s, 3H). LC-MS: method C, RT=2.55 min, MS (ESI) m/z: 535.3 (M+H)⁺.Analytical HPLC purity (method B): 100%.

Example 89 4-fluoro N (2 (2 (2(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

Intermediate 89A: 2-chloro-6-methoxy-4-methylbenzo[d]thiazole

To a solution of copper (II) chloride (1.661 g, 12.35 mmol) inacetonitrile (8 mL) at 40° C. was added tert-butyl nitrite (1.769 mL,13.38 mmol), followed by Intermediate I-3A (2.2 g, 11.33 mmol) as asolid. The mixture was stirring at 40° C. for 2.0 h. HPLC and LCMSindicated a complete conversion of starting material. The mixture wasdiluted with EtOAc, washed with 0.5 HCl, saturated sodium bicarbonateand brine. After evaporation of solvent, Intermediate 89A (2.4 g, 11.23mmol, 99% yield) was obtained as brown solid. ¹H NMR (500 MHz,chloroform-d) δ 7.07 (d, J=2.5 Hz, 1H), 6.93-6.77 (m, 1H), 3.85 (s, 3H),2.66 (s, 3H). LC-MS: method C, RT=2.08 min, MS (ESI) m/z: 213.9 (M+H)⁺.

Intermediate 89B: 2-chloro-4-methylbenzo[d]thiazol-6-ol

Aluminum chloride (4.49 g, 33.7 mmol) was added to a solution ofIntermediate 89A (2.4 g, 11.23 mmol) in toluene (50 mL). The mixture washeated at 110° C. for 1.5 h. TLC indicated a complete conversion ofstarting material. The reaction mixture was cooled to room temperature,quenched with ice-cold 1.0 N HCl (50 mL), stirred at room temperaturefor 30 min. The precipitate was collected by filtration, washed withwater (3×), saturated sodium bicarbonate (3×), water (3×) and air-driedfor 1.0 h under vacuum. It was further dried under high vacuum overnightto give Intermediate 89B as brown solid (2.2 g, 11.02 mmol, 98% yield).

Intermediate 89C:(6-(tert-butyldimethylsilyloxy)-2-chloro-4-methylbenzo[d]thiazole

To a stirred solution of Intermediate 89B (2.2 g, 11.02 mmol) in DMF (50mL) was added TBDMS-Cl (2.325 g, 15.43 mmol) and imidazole (1.313 g,19.28 mmol). The reaction mixture was left stirring at room temperaturefor 1.0 h. HPLC and TLC indicated a clean reaction. The mixture waspartitioned between EtOAc/water. The organic layer was washed withbrine, dried over sodium sulfate. After evaporation of solvent, thecrude product was dissolved in a small amount of chloroform and chargedto a 120 g ISCO column which was eluted with hexanes for 3 min., then a30 min gradient from 0% to 50% EtOAc in hexanes. The desired fractionswere combined and concentrated to give Intermediate 89C (1.57 g, 5.00mmol, 45.4% yield) as a clear orange solid. ¹H NMR (400 MHz,chloroform-d) δ 7.09-6.94 (m, 1H), 6.81 (dd, J=2.5, 0.8 Hz, 1H), 2.64(s, 3H), 1.01 (s, 9H), 0.23 (s, 6H). LC-MS: method C, RT=2.74 min, MS(ESI) m/z: 314 (M+H)⁺.

Intermediate 89D6-(tert-butyldimethylsilyloxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole

To Intermediate I-2 (28 mg, 0.121 mmol), Intermediate 89C (37.9 mg,0.121 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (4.93 mg, 6.03 μmol) was addedtoluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.121 mL, 2M,0.241 mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 135° C. for 40 min. LCMSindicated a clean reaction. To the reaction mixture was addedEtOAc/water/brine. The insoluble was removed by filtration with a pad ofcelite. The organic layers were collected, washed with brine, dried oversodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 12 g ISCOcolumn which was eluted with hexanes for 3 min., then a 20 min gradientfrom 0% to 75% dichloromethane in hexanes The desired fractions werecombined and concentrated to give Intermediate 89D (48 mg, 0.103 mmol,85% yield). LC-MS: method C, gradient time 1 min, RT=2.53 min, MS (ESI)m/z: 466.2 (M+H)⁺.

Intermediate 89E2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol

To a solution of Intermediate 89D (48 mg, 0.103 mmol) in THF (5 mL) atroom temperature was added acetic acid (0.013 mL, 0.227 mmol) followedby addition of 1.0 N TBAF in THF (0.124 mL, 0.124 mmol) dropwise. Themixture was stirred at room temperature for 30 min. LCMS indicated acompletion of reaction. The mixture was diluted with EtOAc, washed withwater, saturated sodium bicarbonate (2×), brine, and dried over sodiumsulfate. After evaporation of the solvent, the crude product waspurified with a 12 g ISCO column eluting with 0% to 80% EtOAc in hexanesfor 15 min. The desired fraction was collected to give Intermediate 89E(36 mg, 0.102 mmol, 99% yield). ¹H NMR (500 MHz, chloroform-d) δ 9.08(s, 1H), 8.93-8.77 (m, 1H), 7.94 (s, 1H), 7.23 (d, J=2.2 Hz, 1H), 6.86(d, J=1.7 Hz, 1H), 4.85 (s, 2H), 3.58 (s, 3H), 2.83 (s, 3H), 2.71 (s,3H). LC-MS: method C, RT=2.21 min, MS (ESI) (m/z) 352 [M+H]⁺

Intermediate 89F: tert-butyl2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate

A solution of DIAD (0.055 mL, 0.282 mmol) in 1 ml of toluene was addeddropwise to a mixture of Intermediate 89E (33 mg, 0.094 mmol),tert-butyl (2-hydroxyethyl)carbamate (18.16 mg, 0.113 mmol) andtriphenylphosphine (49.3 mg, 0.188 mmol) in toluene (1 mL) at 110° C.LCMS indicated a completion of the reaction. The mixture wasconcentrated and purified with a 40 g ISCO column eluted with 0-70%EtOAc in hexanes for 20 min. The desired fraction was collected andconcentrated to give Intermediate 89F (45 mg, 0.091 mmol, 97% yield). ¹HNMR (500 MHz, methanol-d₄) δ 9.05 (s, 1H), 8.79 (d, J=1.7 Hz, 1H), 7.90(s, 1H), 7.28 (d, J=2.5 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H), 4.81 (s, 2H),4.09 (t, J=5.5 Hz, 2H), 3.56 (s, 3H), 3.50 (t, J=5.4 Hz, 2H), 2.78 (s,3H), 2.69 (s, 3H), 1.44 (s, 9H). LC-MS: method C, RT=2.49 min, MS (ESI)(m/z) 495.1 [M+H]⁺.

Intermediate 89G2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethanamine

To a solution of Intermediate 89F (40 mg, 0.081 mmol) in DCM (1 mL) wasadded TFA (1 mL, 12.98 mmol). The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of the reaction.Solvent was removed. The crude sample was diluted with EtOAc and water,extracted with EtOAc, the combined organic layer was washed withsaturated NaHCO₃ and brine, dried with MgSO₄ and concentrated to giveIntermediate 89G (30 mg, 0.076 mmol, 94% yield). ¹H NMR (500 MHz,Methanol-d₄) δ 9.05 (s, 1H), 8.81 (d, J=1.7 Hz, 1H), 7.91 (s, 1H), 7.29(d, J=2.5 Hz, 1H), 6.95 (d, J=1.4 Hz, 1H), 4.80 (s, 2H), 4.26 (t, J=5.1Hz, 2H), 3.54 (s, 3H), 3.35 (t, J=5.0 Hz, 2H), 2.79 (s, 3H), 2.68 (s,3H). LC-MS: method C, RT=1.91 min, MS (ESI) m/z: 395 (M+H)⁺.

Example 89

To a solution of Intermediate 89G (15 mg, 0.038 mmol) and4-fluorobenzene-1-sulfonyl chloride (8.88 mg, 0.046 mmol) in DMF (1 mL)was added DIEA (0.066 mL, 0.380 mmol). The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of the reaction.Solvent was removed, the residual was dissolved purified via preparativeLC/MS (method D, 50-95% B over 10 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to give Example 89 (0.9 mg, 1.629 μmol, 4.28%yield). ¹H NMR (500 MHz, Methanol-d₄) δ 9.06 (s, 1H), 8.80 (d, J=1.9 Hz,1H), 7.95-7.85 (m, 3H), 7.24-7.15 (m, 3H), 6.81 (dd, J=2.2, 0.8 Hz, 1H),4.82 (s, 2H), 4.06 (t, J=5.5 Hz, 2H), 3.57 (s, 3H), 3.35 (t, J=5.5 Hz,2H), 2.77 (s, 3H), 2.70 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI)m/z: 553.2 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 90 4-fluoro N (2 (2 (2methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

Intermediate 90A: tert-butyl2-(4-nitro-3-(trifluoromethyl)phenoxy)ethylcarbamate

DIAD (0.798 mL, 4.10 mmol) was added to a mixture of4-nitro-3-(trifluoromethyl)phenol (0.34 g, 1.642 mmol) in THF (1.0 mL).Next, tert-butyl (2-hydroxyethyl)carbamate (0.529 g, 3.28 mmol) andtriphenylphosphine (0.861 g, 3.28 mmol) in THF (10 mL) were added to theabove mixture using syringe pump in 3 h. The reaction mixture wasstirred at room temperature overnight. LCMS indicated a completion ofthe reaction. The mixture was concentrated and purified with a 40 g ISCOcolumn eluted with 0-70% EtOAc in hexanes for 20 min. The desiredfraction was collected and concentrated to give Intermediate 90A (1.1 g,1.570 mmol, 96% yield) as brown oil. ¹H NMR (400 MHz, chloroform-d) δ8.01 (d, J=9.0 Hz, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.13 (dd, J=9.0, 2.6 Hz,1H), 4.18-4.13 (m, 2H), 3.58 (q, J=5.4 Hz, 2H), 1.45 (s, 9H). LC-MS:method C, RT=2.07 min, MS (ESI) m/z: 251 [M+1-Boc]⁺.

Intermediate 90B: tert-butyl2-(4-amino-3-(trifluoromethyl)phenoxy)ethylcarbamate

To a solution of Intermediate 90A (574 mg, 1.64 mmol) in ethyl acetate(10 mL) under argon was added 10% Pd/C (100 mg, 1.640 mmol). The mixturewas stirred under an atmosphere of hydrogen (balloon) at roomtemperature for 3.0 h. HPLC and TLC indicated a completion of reaction.Pd/C was removed by filtration. The filtrate was concentrated. The crudesample was purified with a 40 g ISCO column eluted with 0-100% EtOAc for20 min. The desired fraction was collected and concentrated to giveIntermediate 90B (670 mg, 1.569 mmol, 96% yield) as dark oil. ¹H NMR(500 MHz, chloroform-d) δ 6.98 (d, J=2.8 Hz, 1H), 6.91 (dd, J=8.7, 2.9Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 6.36 (br. s., 1H), 3.96 (t, J=5.1 Hz,2H), 3.91 (br. s., 2H), 3.50 (d, J=5.0 Hz, 2H), 1.62 (s, 3H). LC-MS:method C, RT=1.83 min, MS (ESI) m/z: 221 (M+H-Boc)⁺.

Intermediate 90C: tert-butyl2-(2-amino-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy) ethylcarbamate

To a solution of Intermediate 90B (180 mg, 0.562 mmol) in acetonitrile(5 mL) was added ammonium thiocyanate (128 mg, 1.686 mmol). The mixturewas stirred at room temperature for 10 min. Benzyltrimethylammoniumtribromide (219 mg, 0.562 mmol) in acetonitrile (2 mL) was addeddropwise (5 min). The mixture was stirred at room temperature overnight.The mixture was diluted with EtOAc and NaHCO₃, extracted with EtOAc. Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude sample was purified with a 12 g ISCO columneluted with 0-100% EtOAc in hexanes for 15 min. The desired fraction wascollected to give Intermediate 90C (100 mg, 0.265 mmol, 47.2% yield) asa white solid. ¹H NMR (500 MHz, methanol-d₄) δ 7.48 (d, J=2.2 Hz, 1H),7.14 (d, J=2.5 Hz, 1H), 4.05 (t, J=5.6 Hz, 2H), 3.43 (t, J=5.5 Hz, 2H),1.44 (s, 9H). ¹⁹F NMR (471 MHz, methanol-d₄) δ −63.25 (s, 3F). LC-MS:method C, RT=1.85 min, MS (ESI) m/z: 378 (M+H)⁺.

Intermediate 90D: tert-butyl(2((2-bromo-4-(trifluoromethyl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate

tert-Butyl nitrite (0.061 mL, 0.464 mmol) was added to copper (II)bromide (101 mg, 0.450 mmol) in dry acetonitrile (2 mL) under argon. Themixture was stirred at room temperature for 10 min. A suspension ofIntermediate 90C (100 mg, 0.265 mmol) in dry acetonitrile (2 mL) wasadded dropwise. The reaction mixture was stirred at room temperatureovernight. LCMS indicated a completion of the reaction. Acetonitrile wasremoved under vacuum, the reaction mixture was diluted with EtOAc,quenched with 1.0 N HCl. The organic layer was collected, washed with0.5 N HCl (2×), saturated sodium bicarbonate, brine, dried over sodiumsulfate. After evaporation of solvent, the crude sample was purifiedwith a 40 g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min.The desired fraction was collected and concentrated to give Intermediate90D (92 mg, 0.208 mmol, 79% yield) as a white solid. LC-MS: method C,RT=2.20 min, MS (ESI) m/z: 547.2 (M+H)⁺.

Intermediate 90E: tert-butyl2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy)ethylcarbamate

To Intermediate I-1 (15.24 mg, 0.045 mmol), and Intermediate 90D (20 mg,0.045 mmol) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)complex with dichloromethane (1:1) (1.851 mg, 2.266 μmol) was addedtoluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.045 mL, 2M,0.091 mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 135° C. for 40 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layers were collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 12 g ISCO column which was eluted with hexanes for 3min., then a 20 min gradient from 0% to 75% dichloromethane in hexanes.The desired fractions were combined and concentrated to giveIntermediate 90E (25.9 mg, 0.045 mmol, 100% yield) as a bright yellowsolid. LC-MS: method C, gradient time 1 min, RT=1.67 min, MS (ESI) m/z:571 (M+H)⁺.

Intermediate 90F: tert-butyl2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy)ethylcarbamate

To a solution of Intermediate 90E (25.7 mg, 0.045 mmol) in THF (1 mL)was added sodium methoxide (0.090 mL, 0.5M, 0.045 mmol) and the mixturewas stirred at room temperature for 1 h. LCMS indicated a completion ofthe reaction. The mixture was diluted with DCM and water, extracted withDCM and the combined organic layer was washed with brine, dried overMgSO₄ and concentrated. The crude sample was purified with a 12 g ISCOcolumn eluted with 0-70% EtOAc in hexanes for 15 min. The desiredfraction was collected and concentrated to give Intermediate 90F (10 mg,0.019 mmol, 41.6% yield) as a white solid. ¹H NMR (500 MHz, Methanol-d₄)δ 8.63 (s, 1H), 8.51 (s, 1H), 7.75 (s, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.39(s, 1H), 4.14 (t, J=5.5 Hz, 2H), 4.11 (s, 3H), 3.52 (t, J=5.4 Hz, 2H),2.64 (s, 3H), 1.44 (s, 9H). LC-MS: method C, R=2.66 min, MS (ESI) m/z:535 (M+H)⁺.

Intermediate 90G:2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(trifluoromethyl)benzo[d]thiazol-6-yloxy)ethanamine

To a solution of Intermediate 90F (7 mg, 0.013 mmol) in DCM (1 mL) wasadded TFA (0.020 mL, 0.262 mmol). The mixture was stirred at roomtemperature for 5 h. Solvent was removed and Intermediate 90G was usedfor next step without purification. LC-MS: method C, RT=2.15 min, MS(ESI) m/z: 435 (M+H)⁺.

Example 90

To a solution of Intermediate 90G (5.65 mg, 0.013 mmol) and4-fluorobenzene-1-sulfonyl chloride (3.04 mg, 0.016 mmol) in DMF (1 mL)was added DIEA (0.023 mL, 0.130 mmol). The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of the reaction.Solvent was removed, the residual was purified via preparative LC/MS(method D, 55-95% B over 10 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to give Example 90 (4.4 mg, 7.43 μmol, 57.1%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 (s, 1H), 7.72 (d, J=1.7 Hz,1H), 7.16 (d, J=2.5 Hz, 1H), 7.13-7.03 (m, 3H), 6.59-6.54 (m, 2H), 6.42(d, J=2.2 Hz, 1H), 3.30 (t, J=5.2 Hz, 2H), 3.26 (s, 3H), 2.45 (br. s.,2H), 1.82 (s, 3H). LC-MS: method C, RT=2.54 min, MS (ESI) m/z: 593.1(M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 91N-(2-(2-(2-cyclopropyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide

Intermediate 91A: tert-butyl(2-bromo-4-methyl-6-nitrophenyl)(2-cyclopropyl-2-oxoethyl)carbamate

To Intermediate I-1B (400 mg, 1.208 mmol) in DMF (5 mL) at roomtemperature was added Cs₂CO₃ (1181 mg, 3.62 mmol). The brown solutionwas stirred at room temperature for 5 min, followed by addition of2-bromo-1-cyclopropylethanone (438 mg, 2.416 mmol) in acetonitrile (0.4mL). The mixture was stirred at room temperature for 2 h. TLC and LCMSindicated a clean reaction. The mixture was diluted with EtOAc, washedwith water, brine, dried over sodium sulfate and concentrated. The crudesample was purified with a 40 g ISCO column eluted with 0-100% EtOAc inhexanes for 20 min. The desired fraction was collected and concentratedto give Intermediate 91A (490 mg, 1.186 mmol, 98% yield) as yellow oil.LC-MS: method C, RT=2.03 min, MS (ESI) m/z: 356 and 358 [M+1-tBu]⁺.

Intermediate 91B: 5-bromo-2-cyclopropyl-7-methylquinoxaline

To Intermediate 91A (490 mg, 1.186 mmol) in DCM (4 mL) was added 4.0 NHCl in dioxane (3.56 mL, 14.23 mmol) and the mixture was stirred at roomtemperature for 1 h. TLC indicated a completion of the reaction. Solventwas removed to give the deprotected intermediate as yellow oil. Thedeprotected intermediate was dissolved in THF (4 mL). Tin(II) chloridedihydrate (883 mg, 3.91 mmol) was added followed by concentrated HCl(0.146 mL, 1.779 mmol). The mixture was placed and stirred in an oilbath pre-heated at 45° C. for 1.0 h. TLC and LCMS indicated a cleanreaction. The reaction mixture was diluted with EtOAc/water andneutralized with saturated sodium bicarbonate. The mixture was stirredat room temperature for 15 min and extracted with EtOAc (5×). Theprecipitate (tin hydroxide) was removed by a separatory funnel. Theorganic layer was washed with saturated sodium bicarbonate, brine, driedover sodium sulfate and concentrated. The crude sample was purified witha 40 g ISCO column eluted with 0-60% EtOAc in hexanes for 15 min. Thedesired fraction was collected and concentrated to give Intermediate 91B(310 mg, 1.178 mmol, 99% yield) as a light yellow solid. ¹H NMR (400MHz, chloroform-d) δ 8.76 (s, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.69 (dd,J=1.8, 0.9 Hz, 1H), 2.54 (s, 3H), 2.34-2.23 (m, 1H), 1.30-1.25 (m, 2H),1.24-1.16 (m, 2H). LC-MS: method C, RT=2.07 min, MS (ESI) m/z: 263 and265. (M+H)⁺.

Intermediate 91C2-cyclopropyl-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

A mixture of Intermediate 91B (30 mg, 0.114 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (50.7 mg,0.200 mmol), potassium acetate (22.38 mg, 0.228 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (2.79 mg, 3.42 μmol) in dioxane (2 mL) wasdegassed with argon for 10 min. The reaction vial was heated inmicrowave reactor at 120° C. for 30 min. LCMS indicated completeconversion of starting material and a clean reaction. The mixture wasdiluted with EtOAc/water, insoluble material was removed by filtration.The filtrate was extracted with EtOAc, washed with brine, dried oversodium sulfate. After evaporation of solvent, the crude sample ofIntermediate 91C was obtained and used for the next step withoutpurification. LC-MS: method C, RT=2.03 min, MS (ESI) m/z: 229 (M+H)⁺(boronic acid).

Example 91

To Intermediate 91C (34.8 mg, 0.112 mmol), Intermediate I-5 (20 mg,0.045 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (1.834 mg, 2.246 μmol) was addedtoluene (3 mL), EtOH (1 mL) and sodium carbonate (0.045 mL, 2M, 0.090mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 130° C. for 40 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layers were collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was purified via preparative LC/MS (method D,60-100% B over 20 min., then a 5-min hold at 100% B). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give Example 91 (6.8 mg, 0.012 mmol, 27.6% yield). ¹H NMR(500 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.67 (s, 1H), 8.03 (br. s., 1H),7.95-7.81 (m, 3H), 7.48-7.37 (m, 3H), 6.85 (s, 1H), 4.05 (t, J=5.0 Hz,2H), 3.22 (br. s., 2H), 2.72 (s, 3H), 2.64 (s, 3H), 1.29-1.13 (m, 5H).LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 549.2 (M+H)⁺. AnalyticalHPLC purity (method B): 99%.

Example 92 Benzyl2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate

Intermediate 92A: tert-butyl 2-(3-methyl-4-nitrophenoxy)ethylcarbamate

A solution of DIAD (7.77 mL, 40.0 mmol) in 2 ml of toluene was added toa mixture of 3-methyl-4-nitrophenol (3.4 g, 22.20 mmol), tert-butyl(2-hydroxyethyl) carbamate (4.29 g, 26.6 mmol) and triphenylphosphine(6.99 g, 26.6 mmol) in toluene (50 mL) at 110° C. using syringe pump in2 h. The reaction mixture was stirred at 110° C. for additional 30 min,then at room temperature overnight. The mixture was diluted with EtOAcand water, extracted with EtOAc, the combined organic layer was washedwith NaHCO₃ and brine, dried with Na₂SO₄ and concentrated. The crudesample was purified with a 120 g ISCO column eluted with 0-70% EtOAc inhexanes for 40 min. The desired fraction was collected and concentratedto give Intermediate 92A (3.3 g, 11.14 mmol, 50.2% yield). ¹H NMR (500MHz, chloroform-d) δ 8.08 (d, J=8.8 Hz, 1H), 6.84-6.77 (m, 2H), 4.97(br. s., 1H), 4.09 (t, J=5.1 Hz, 2H), 3.56 (q, J=5.0 Hz, 2H), 2.63 (s,3H), 1.46 (s, 9H). LC-MS: method C, RT=2.03 min, MS (ESI) m/z: 197(M+H-Boc)⁺.

Intermediate 92B: tert-butyl 2-(4-amino-3-methylphenoxy)ethylcarbamate

To a solution of Intermediate 92A (3.5 g, 11.81 mmol) in ethyl acetate(10 mL) under argon was added 10% Pd/C (200 mg, 23.62 mmol). The mixturewas stirred under an atmosphere of hydrogen (balloon) at roomtemperature overnight. Pd/C was removed by filtration. The filtrate wasconcentrated. The crude sample was purified with a 120 g ISCO columneluted with 0-100% EtOAc in hexanes for 45 min. The desire fraction wascollected to give Intermediate 92B (2.5 g, 9.39 mmol, 79% yield) as apink solid. ¹H NMR (500 MHz, chloroform-d) δ 6.67 (s, 1H), 6.62 (d,J=1.7 Hz, 2H), 5.00 (br. s., 1H), 3.95 (t, J=5.1 Hz, 2H), 3.49 (d, J=5.0Hz, 2H), 3.37 (br. s., 2H), 2.16 (d, J=0.6 Hz, 3H), 1.46 (s, 9H). LC-MS:method C, RT=1.34 min, MS (ESI) m/z: 167 [M+1-Boc]⁺.

Intermediate 92C: tert-butyl2-(2-amino-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate

To a solution of Intermediate 92B (2.5 g, 9.39 mmol) in acetonitrile (20mL) was added ammonium thiocyanate (1.072 g, 14.08 mmol). The mixturewas stirred at room temperature for 10 min. Benzyltrimethylammoniumtribromide (3.66 g, 9.39 mmol) in acetonitrile (10 mL) was addeddropwise (5 min). The mixture was stirred at room temperature overnight.LCMS indicated a clean reaction. The mixture was diluted withEtOAc/saturated sodium bicarbonate. The insoluble material was removedby filtration. The organic layer of the filtrate was collected, washedwith brine, dried over sodium sulfate. After evaporation of solvent, theproduct was precipitated out from methanol, collected by filtration,washed with acetonitrile to give Intermediate 92C (2.8 g, 8.66 mmol, 92%yield) as a slightly yellow solid. ¹H NMR (500 MHz, chloroform-d) δ 6.97(d, J=2.2 Hz, 1H), 6.75 (d, J=1.9 Hz, 1H), 5.05 (s, 2H), 4.02 (t, J=5.0Hz, 2H), 3.53 (d, J=4.7 Hz, 2H), 2.53 (s, 3H), 1.46 (s, 9H). LC-MS:method C, RT=2.57 min, MS (ESI) m/z: 324 (M+H)⁺.

Intermediate 92D: tert-butyl2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate

To a stirred solution of Intermediate 92C (2.8 g, 8.66 mmol) and copper(II) chloride (1.029 g, 10.39 mmol) in acetonitrile (30 mL) was addedtert-butyl nitrite (1.487 mL, 11.26 mmol). The mixture was stirred atroom temperature for 2 h. Acetonitrile was removed under vacuum, thereaction mixture was diluted with EtOAc, quenched with 1.0 N HCl. Theorganic layer was collected, washed with 0.5 N HCl (2×), saturatedsodium bicarbonate, brine, dried over sodium sulfate. After evaporationof solvent, the crude dark oil was purified with a 120 g ISCO columneluted with 0-70% EtOAc in hexanes for 40 min. The desired fraction wascollected and concentrated to give Intermediate 92D (1.75 g, 5.10 mmol,59.0% yield) as an off-white solid. ¹H NMR (500 MHz, chloroform-d) δ7.05 (d, J=2.5 Hz, 1H), 6.89 (dd, J=2.5, 0.8 Hz, 1H), 5.00 (br. s., 1H),4.05 (t, J=5.1 Hz, 2H), 3.56 (d, J=5.0 Hz, 2H), 2.65 (s, 3H), 1.46 (s,9H). LC-MS: method C, RT=2.21 min, MS (ESI) m/z: 343 (M+H)⁺.

Intermediate 92E: 2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethanamine

To a solution of Intermediate 92D (100 mg, 0.292 mmol) in DCM (1.5 mL)was added TFA (1.124 mL, 14.58 mmol). The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of the reaction. Themixture was concentrated and the residual was diluted with EtOAc andsaturated NaHCO₃, extracted with EtOAc. The combined organic layer waswashed with brine, dried with MgSO₄ and concentrated to giveIntermediate 92E (70 mg, 0.288 mmol, 99% yield) as an off-white solid.¹H NMR (400 MHz, Methanol-d₄) δ 7.29 (d, J=2.4 Hz, 1H), 7.06-6.84 (m,1H), 4.19 (t, J=5.2 Hz, 2H), 3.28 (br. s., 2H), 2.58 (s, 3H). LC-MS:method C, RT=1.43 min, MS (ESI) m/z: 243 (M+H)⁺.

Intermediate 92F: benzyl2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate

To a stirred solution of Intermediate 92E (70 mg, 0.288 mmol) in THF (1mL) at room temperature was added sodium bicarbonate (1.154 mL, 2M,2.307 mmol). CBz-Cl (0.049 mL, 0.346 mmol) was added dropwise. Themixture was stirred at room temperature for 1 h, LCMS indicated acompletion of the reaction. The mixture was diluted with EtOAc andwater, extracted with EtOAc. The combined organic layer was washed withbrine, dried with MgSO₄ and concentrated. The crude sample was purifiedwith a 12 g ISCO column eluted with 0-60% EtOAc in hexanes for 15 min.The desired product was collected and concentrated to give Intermediate92F (100 mg, 0.265 mmol, 92% yield). ¹H NMR (400 MHz, chloroform-d) δ7.38-7.35 (m, 5H), 7.04 (d, J=2.2 Hz, 1H), 6.87 (d, J=1.3 Hz, 1H), 5.25(br. s., 1H), 5.12 (s, 2H), 4.72 (s, 1H), 4.07 (t, J=5.1 Hz, 2H), 3.64(q, J=5.3 Hz, 2H), 2.65 (s, 3H). LC-MS: method C, RT=2.22 min, MS (ESI)m/z: 377 (M+H)⁺.

Example 92

To Intermediate I-2 (30 mg, 0.129 mmol), Intermediate 92F (58.5 mg,0.155 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.28 mg, 6.46 μmol) was addedtoluene (3 mL), EtOH (1 mL) and sodium carbonate (0.129 mL, 2M, 0.259mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 130° C. for 40 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layers were collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 40 g ISCO column which was eluted with hexanes for 3min., then a 20 min gradient from 0% to 100% EtOAc in hexanes Thedesired fractions were combined and concentrated. The sample was furtherpurified via preparative LC/MS (method D, 50-90% B over 10 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 92 (42mg, 0.079 mmol, 61.5% yield) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.08 (s, 1H), 8.80 (s, 1H), 8.01 (s, 1H), 7.60-7.48 (m, 2H),7.36 (d, J=4.4 Hz, 4H), 7.33-7.28 (m, 1H), 7.00 (br. s., 1H), 5.05 (s,2H), 4.80 (s, 2H), 4.10 (t, J=5.5 Hz, 2H), 3.48-3.41 (m, 5H), 2.74 (s,3H), 2.70 (s, 3H). LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 529.2(M+H)⁺.

Example 934-chloro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 93A: 2-chloro-4-methoxy-1-nitrobenzene

To a solution of 2-chloro-4-fluoro-1-nitrobenzene (220 mg, 1.253 mmol)in THF (2 mL) was added sodium methoxide (7.52 mL, 0.5, 3.76 mmol). Themixture was stirred at room temperature for 1.0 h. LCMS indicated acompletion of the reaction The mixture was diluted with EtOAc, quenchedwith saturated ammonium chloride. The organic layer was washed withsaturated sodium bicarbonate, brine, dried over sodium sulfate andconcentrated. The crude product was purified with flash chromatography(loading in chloroform, 0% to 30% EtOAc in hexanes over 12 min using a12 g silica gel cartridge). The desired fractions were combined andconcentrated to give Intermediate 93A (230 mg, 1.226 mmol, 98% yield) asa yellow liquid. ¹H NMR (400 MHz, chloroform-d) δ 8.02 (d, J=9.2 Hz,1H), 7.03 (d, J=2.6 Hz, 1H), 6.89 (dd, J=9.2, 2.6 Hz, 1H), 3.90 (s, 3H).LC-MS: method C, RT=1.80 min, MS (ESI) m/z: 188 (M+H)⁺.

Intermediate 93B: 2-chloro-4-methoxyaniline

To a solution of Intermediate 93A (230 mg, 1.226 mmol) in MeOH (6.0 mL)was added ammonium chloride (1312 mg, 24.52 mmol) and zinc dust (802 mg,12.26 mmol). The mixture was stirred at room temperature for 1 h. MeOHwas removed under vacuum. The residue was diluted with EtOAc/saturatedsodium bicarbonate and stirred at room temperature for 10 min. Themixture was filtered to remove insoluble material. The filtrate wascollected, organic layer was washed with brine, dried over sodiumsulfate and concentrated. The crude sample was purified with a 12 g ISCOcolumn eluted with 0-100% EtOAc in hexanes for 15 min. The desiredfraction was collected and concentrated to give Intermediate 93B (193mg, 1.225 mmol, 100% yield) as oil. ¹H NMR (400 MHz, chloroform-d) δ6.86 (t, J=2.5 Hz, 1H), 6.76-6.64 (m, 2H), 3.74 (d, J=3.1 Hz, 3H).LC-MS: method C, RT=0.8 min, MS (ESI) m/z: 158 (M+H)⁺.

Intermediate 93C: 4-chloro-6-methoxybenzo[d]thiazol-2-amine

To a solution of Intermediate 93B (190 mg, 1.206 mmol) in acetonitrile(5.0 mL) was added ammonium thiocyanate (161 mg, 2.110 mmol). Themixture was stirred at room temperature for 10 min.Benzyltrimethylammonium tribromide (635 mg, 1.628 mmol) in acetonitrile(2.0 mL) was added dropwise (5 min). The mixture was stirred at roomtemperature overnight. Acetonitrile was removed under vacuum. Themixture was diluted with EtOAc, THF/saturated sodium bicarbonate. Theinsoluble material was removed by filtration. The organic layer of thefiltrate was collected, washed with brine, dried over sodium sulfate andconcentrated to give Intermediate 93C (250 mg, 1.165 mmol, 97% yield) asa yellow solid that was used for the next step without furtherpurification. ¹H NMR (400 MHz, methanol-d₄) δ 7.16 (d, J=2.4 Hz, 1H),6.91 (d, J=2.4 Hz, 1H), 3.79 (s, 3H). LC-MS: method C, RT=1.38 min, MS(ESI) m/z: 215 (M+H)⁺.

Intermediate 93D: 2-bromo-4-chloro-6-methoxybenzo[d]thiazole

To a solution of copper (II) bromide (0.21 g, 1.51 mmol) in acetonitrile(8 mL) at 40° C. was added tert-butyl nitrite (0.200 mL, 1.514 mmol)followed by Intermediate 93C (250 mg, 1.165 mmol) as a solid. Themixture was stirring at 40° C. for 2.0 h. HPLC and LCMS indicated acomplete conversion of starting material. The mixture was diluted withEtOAc, washed with 0.5 HCl, saturated sodium bicarbonate and brine.After evaporation of solvent, Intermediate 93D (215 mg, 0.772 mmol,66.3% yield) was obtained as a yellow solid. ¹H NMR (400 MHz,chloroform-d) δ 7.17 (d, J=2.4 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 3.87 (s,3H). LC-MS: method C, RT=2.08 min, MS (ESI) m/z: 279.9 (M+H)⁺.

Example 93

To Intermediate I-2 (11 mg, 0.047 mmol), Intermediate 93D (15.85 mg,0.057 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (1.936 mg, 2.370 μmol) was addedtoluene (3 mL), EtOH (1 mL) and sodium carbonate (0.047 mL, 2M, 0.095mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 130° C. for 40 min. LCMSindicated a clean reaction. To the reaction mixture was addedEtOAc/water/brine. The insoluble was removed by filtration with a pad ofcelite. The organic layers were collected, washed with brine, dried oversodium sulfate. After evaporation of solvent, the crude product waspurified via preparative LC/MS (method D, 45-85% B over 20 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 93 (3.3mg, 8.47 μmol, 17.86% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 1H),8.80 (d, J=1.7 Hz, 1H), 8.07 (s, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.32 (d,J=2.2 Hz, 1H), 4.82 (s, 2H), 3.89 (s, 3H), 3.47 (s, 3H), 2.70 (s, 3H).LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 386.1 (M+H)⁺. AnalyticalHPLC purity (method B): 99%.

Example 945-(5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline

To Intermediate I-2E (5 mg, 0.019 mmol),(5-methoxybenzofuran-2-yl)boronic acid (4.31 mg, 0.022 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (0.764 mg, 0.936 μmol) was added toluene(0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.019 mL, 2M, 0.037mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 130° C. for 40 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layers were collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was purified via preparative LC/MS (method D;50-90% B over 10 min., then a 5-min hold at 100% B). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give Example 94 (5.1 mg, 0.014 mmol, 75.0% yield). ¹H NMR(500 MHz, DMSO-d₆) δ 9.07 (s, 1H), 8.28 (d, J=1.7 Hz, 1H), 8.15 (s, 1H),7.89 (s, 1H), 7.61-7.58 (m, 1H), 7.31 (d, J=2.5 Hz, 1H), 6.98-6.96 (m,1H), 4.80 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.47 (s, 3H). LC-MS:method C, RT=2.36 min, MS (ESI) m/z: 335.10 (M+H)⁺. Analytical HPLCpurity (method B): 92%.

Example 95N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Intermediate 95A: tert-butyl2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbamate

To Intermediate I-2 (40 mg, 0.172 mmol), Intermediate 92D (59.1 mg,0.172 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (7.04 mg, 8.62 μmol) was addedtoluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.172 mL, 2M,0.345 mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 130° C. for 40 min. LCMSindicated a clean reaction. To the reaction mixture was addedEtOAc/water/brine. The insoluble was removed by filtration with a pad ofcelite. The organic layers were collected, washed with brine, dried oversodium sulfate. After evaporation of solvent, the crude product wasdissolved in a small amount of chloroform and charged to a 40 g ISCOcolumn which was eluted with hexanes for 3 min., then a 20 min gradientfrom 0% to 100% EtOAc in hexanes. The desired fractions were combinedand concentrated to give Intermediate 95A (80 mg, 0.162 mmol, 94%yield). ¹H NMR (400 MHz, chloroform-d) δ 9.06 (d, J=3.5 Hz, 1H), 8.85(d, J=3.3 Hz, 1H), 7.92 (br. s., 1H), 7.23 (t, J=2.6 Hz, 1H), 6.93 (br.s., 1H), 5.07 (br. s., 1H), 4.83 (d, J=2.4 Hz, 2H), 4.12-4.05 (m, 2H),3.60-3.53 (m, 5H), 2.83 (s, 3H), 2.70 (d, J=2.0 Hz, 3H), 1.48 (s, 9H).LC-MS: method C, RT=2.50 min, MS (ESI) m/z: 495 (M+H)⁺.

Intermediate 95B2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethanamine

To a solution of Intermediate 95A (18 mg, 0.036 mmol) in DCM (1 mL) wasadded 2,6-lutidine (16.95 μl, 0.146 mmol) followed by TMS-OTf (13.15 μl,0.073 mmol) at room temperature. The mixture was stirred at roomtemperature overnight. Another portion of TMS-OTf (13.15 μl, 0.073 mmol)was added to the mixture, and the mixture was stirred at roomtemperature for 2 h. LCMS indicated a completion of the reaction. Themixture was diluted with EtOAc and NaHCO₃, extracted with EtOAc. Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated to give Intermediate 95B (14.2 mg, 0.036 mmol, 98% yield).The sample was used for next step without further purification. ¹H NMR(400 MHz, Methanol-d₄) δ 9.06 (s, 1H), 8.82 (d, J=1.8 Hz, 1H), 7.93 (s,1H), 7.36 (d, J=2.4 Hz, 1H), 6.99 (dd, J=2.4, 0.9 Hz, 1H), 4.82-4.81 (m,2H), 4.15 (t, J=5.2 Hz, 2H), 3.15 (t, J=5.1 Hz, 2H), 2.79 (s, 3H), 2.70(s, 3H). LC-MS: method C, RT=1.43 min, MS (ESI) m/z: 243 (M+H)⁺.

Example 95

To a solution of Intermediate 95B (14.20 mg, 0.036 mmol) in DMF (1 mL)was added DIEA (0.063 mL, 0.360 mmol) and benzenesulfonyl chloride (5.57μl, 0.043 mmol). The mixture was stirred at room temperature for 1 h.The reaction mixture was quenched with 0.2 ml of MeOH. Solvent wasremoved, the residual was purified via preparative LC/MS (method D,50-90% B over 12 min., then a 5-min hold at 100% B). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give Example 95 (3.3 mg, 6.05 μmol, 16.80% yield). ¹H NMR(500 MHz, methanol-d₄) δ 9.06 (s, 1H), 8.80 (d, J=1.5 Hz, 1H), 7.97-7.84(m, 3H), 7.55 (d, J=7.4 Hz, 1H), 7.52-7.47 (m, 2H), 7.15 (d, J=2.0 Hz,1H), 6.81 (d, J=1.5 Hz, 1H), 4.82 (s, 2H), 4.04 (t, J=5.4 Hz, 2H), 3.57(s, 3H), 3.35 (t, J=5.7 Hz, 2H), 2.76 (s, 3H), 2.69 (s, 3H). LC-MS:method C, RT=2.43 min, MS (ESI) m/z: 535.15 (M+H)⁺. Analytical HPLCpurity (method B): 98%.

Example 96 2-fluoro N (2 (2 (2(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

To a solution of Intermediate 95B (8 mg, 0.020 mmol) in DMF (1 mL) wasadded DIEA (0.035 mL, 0.203 mmol) and 2-fluorobenzene-1-sulfonylchloride (4.74 mg, 0.024 mmol). The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of the reaction.Solvent was removed, the residual was purified via preparative LC/MS(method D, 50-90% B over 10 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to give Example 96 (4.2 mg, 7.60 μmol, 37.5%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.78 (d, J=1.9 Hz,1H), 8.01 (d, J=0.8 Hz, 1H), 7.84 (td, J=7.6, 1.7 Hz, 1H), 7.74-7.65 (m,1H), 7.43-7.34 (m, 3H), 6.76 (d, J=1.4 Hz, 1H), 4.80 (s, 2H), 4.05 (t,J=5.4 Hz, 2H), 3.46 (s, 3H), 3.35-3.33 (m, 2H), 2.74-2.71 (m, 3H), 2.68(s, 3H). LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 553.1 (M+H)⁺.Analytical HPLC purity (method B): 100%.

Example 973-fluoro-N-(2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

To a solution of Intermediate 95B (8 mg, 0.020 mmol) in DMF (1 mL) wasadded DIEA (0.035 mL, 0.203 mmol) and 3-fluorobenzene-1-sulfonylchloride (4.74 mg, 0.024 mmol). The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of the reaction.Solvent was removed, the residual was purified via preparative LC/MS(method D, 50-90% B over 10 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to give Example 97 (4.1 mg, 7.34 μmol, 36.2%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.80 (d, J=1.9 Hz,1H), 8.14 (br. s., 1H), 8.02 (s, 1H), 7.73-7.61 (m, 3H), 7.50 (s, 1H),7.45 (s, 1H), 6.86 (d, J=1.4 Hz, 1H), 4.81 (s, 2H), 4.06 (t, J=5.4 Hz,2H), 3.47 (s, 3H), 3.26 (d, J=5.0 Hz, 2H), 2.74 (s, 3H), 2.69 (s, 3H).LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 553.1 (M+H)⁺. AnalyticalHPLC purity (method B): 99%.

Example 98N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)methanesulfonamide

Intermediate 98A: tert-butyl 2-(3-chloro-4-nitrophenoxy)ethylcarbamate

To a solution of tert-butyl (2-hydroxyethyl)carbamate (3.67 g, 22.79mmol) in THF (30 mL) was added 1 N sodium bis(trimethylsilyl)amide inTHF (25.06 mL, 25.06 mmol). The mixture was stirred at room temperaturefor 10 min. 2-Chloro-4-fluoro-1-nitrobenzene (2 g, 11.39 mmol) was addedand the reaction mixture was stirred at room temperature for 2 h. Themixture was diluted with EtOAc, quenched with saturated ammoniumchloride. The organic layer was washed with saturated sodiumbicarbonate, brine, dried over sodium sulfate and concentrated. Thecrude product was purified with flash chromatography (loading inchloroform, 0% to 45% EtOAc in hexanes over 15 min using a 120 g silicagel cartridge). The desired fractions were combined and concentrated toyield Intermediate 98A (3.6 g, 11.37 mmol, 100% yield) as a yellowliquid. ¹H NMR (400 MHz, chloroform-d) δ 8.10-7.87 (m, 1H), 7.03 (d,J=2.4 Hz, 1H), 6.88 (dd, J=9.0, 2.6 Hz, 1H), 4.94 (br. s., 1H),4.11-4.02 (m, 2H), 3.57 (q, J=5.4 Hz, 2H), 1.46 (s, 9H). LC-MS: methodC, RT=2.04 min, MS (ESI) m/z: 217 [M+1-Boc]⁺.

Intermediate 98B: tert-butyl 2-(4-amino-3-chlorophenoxy)ethylcarbamate

To a solution of Intermediate 98A (3.6 g, 11.37 mmol) in MeOH (6.0 mL)was added ammonium chloride (7.30 g, 136 mmol) and zinc dust (4.46 g,68.2 mmol). The mixture was stirred at room temperature overnight. MeOHwas removed. The residue was diluted with EtOAc/saturated sodiumbicarbonate and stirred at room temperature for 10 min. The mixture wasfiltered to remove insoluble material. The filtrate was collected,organic layer was washed with brine, dried over sodium sulfate andconcentrated. The crude sample was purified with a 120 g ISCO columneluted with 0-100% EtOAc in hexanes for 40 min. The desired fraction wascollected and concentrated to give Intermediate 98B (2.9 g, 10.11 mmol,89% yield) as off-white solid. ¹H NMR (400 MHz, chloroform-d) δ 6.86 (d,J=2.4 Hz, 1H), 6.80-6.65 (m, 2H), 3.94 (t, J=5.2 Hz, 2H), 3.49 (q, J=4.9Hz, 2H), 1.46 (s, 9H). LC-MS: method C, RT=1.52 min, MS (ESI) m/z: 187[M+1-B0c]⁺.

Intermediate 98C: tert-butyl2-(2-amino-4-chlorobenzo[d]thiazol-6-yloxy)ethylcarbamate

To Intermediate 98B (2.9 g, 10.11 mmol) in acetonitrile (30 mL) wasadded ammonium thiocyanate (1.347 g, 17.70 mmol). The mixture wasstirred at room temperature for 10 min. Benzyltrimethylammoniumtribromide (5.32 g, 13.65 mmol) in acetonitrile (2.0 mL) was addeddropwise (5 min). The mixture was stirred at room temperature overnight.Acetonitrile was removed. The residual was diluted with EtOAc andsaturated sodium bicarbonate, extracted with EtOAc (3×). The combinedorganic layer was washed with brine, dried over sodium sulfate andconcentrated to give Intermediate 98C (2.8 g, 8.14 mmol, 81% yield) as ayellow solid that was used for the next step without furtherpurification. ¹H NMR (400 MHz, Methanol-d₄) δ 7.02 (d, J=2.4 Hz, 1H),6.90 (d, J=2.2 Hz, 1H), 3.97 (t, J=5.4 Hz, 2H), 3.48-3.39 (m, 2H), 1.41(s, 9H). LC-MS: method C, RT=1.71 min, MS (ESI) m/z: 344 (M+H)⁺.

Intermediate 98D: tert-butyl 2-(2-bromo-4-chlorobenzo[d]thiazol-6-yloxy)ethylcarbamate

To a solution of copper (II) bromide (1.402 g, 9.77 mmol) inacetonitrile (30 mL) at 40° C. was added tert-butyl nitrite (1.399 mL,10.59 mmol) followed by Intermediate 98C (2.8 g, 8.14 mmol) as a solid.The mixture was stirring at 40° C. for 2.0 h and then room temperatureovernight. The mixture was diluted with EtOAc, washed with 0.5 HCl,saturated sodium bicarbonate and brine. After evaporation of solvent,the crude sample was purified with a 40 g ISCO column eluted with 0-70%EtOAc in hexanes for 20 min. The desired fraction was collected andconcentrated to give Intermediate 98D (240 mg, 0.589 mmol, 7.23% yield).¹H NMR (400 MHz, chloroform-d) δ 7.15 (d, J=2.4 Hz, 1H), 7.11 (d, J=2.4Hz, 1H), 4.06 (t, J=5.2 Hz, 2H), 3.56 (q, J=5.3 Hz, 2H), 1.46 (s, 9H).LC-MS: method C, RT=2.21 min, MS (ESI) m/z: 406.9 and 408.9 (M+H)⁺.

Intermediate 98E: tert-butyl2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethylcarbamate

To Intermediate I-2 (40 mg, 0.172 mmol), Intermediate 98D (70.3 mg,0.172 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (7.04 mg, 8.62 μmol) was addedtoluene (1.5 mL), EtOH (0.5 mL) and sodium carbonate (0.172 mL, 2M,0.345 mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 120° C. for 40 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layers were collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 40 g ISCO column which was eluted with hexanes for 3min., then a 20 min gradient from 0% to 100% EtOAc in hexanes. Thedesired fraction was collected and concentrated to give Intermediate 98E(85 mg, 0.165 mmol, 96% yields). ¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (s,1H), 8.80 (d, J=1.7 Hz, 1H), 8.06 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.29(d, J=2.2 Hz, 1H), 7.05 (br. s., 1H), 4.81 (s, 2H), 4.10 (t, J=5.6 Hz,2H), 3.47 (s, 3H), 3.39-3.34 (m, 2H), 2.70 (s, 3H), 1.39 (s, 9H). LC-MS:method C, RT=2.54 min, MS (ESI) m/z: 515 (M+H)⁺.

Intermediate 98F:2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethanamine

To a solution of Intermediate 98E (85 mg, 0.165 mmol) in DCM (2 mL) wasadded 2,6-lutidine (0.058 mL, 0.495 mmol) followed by TMS-OTf (0.135 mL,0.75 mmol) at 0° C. The mixture was stirred at room temperature for 2 h.LCMS indicated a completion of the reaction. The mixture was dilutedwith EtOAc and NaHCO₃, extracted with EtOAc. The combined organic layerwas washed with brine and concentrated. The residual was added 1 ml ofMeOH and stirred at room temperature for 15 min and concentrated to giveIntermediate 98F (65 mg, 0.157 mmol, 95% yield) as a yellow solid. thecrude sample was used for next step without purification. ¹H NMR (400MHz, Methanol-d₄) δ 9.04 (s, 1H), 8.90-8.82 (m, 1H), 7.92 (s, 1H), 7.38(d, J=2.2 Hz, 1H), 7.19 (d, J=2.2 Hz, 1H), 4.81 (s, 2H), 4.10 (t, J=5.0Hz, 2H), 3.56 (s, 3H), 3.10 (br. s., 2H), 2.69 (s, 3H). LC-MS: method C,RT=1.91 min, MS (ESI) m/z: 415 (M+H)⁺.

Example 98

To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in DMF (1 mL)was added DIEA (0.052 mL, 0.300 mmol) and methanesulfonyl chloride (4.12mg, 0.036 mmol). The mixture was stirred at room temperature for 15 min.The reaction was quenched with water, and the solvent was removed. Theresidual was purified via preparative LC/MS (method D, 55-95% B over 10min., then a 5-min hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to giveExample 98 (6.2 mg, 0.013 mmol, 41.9% yield). ¹H NMR (500 MHz, DMSO-d₆)δ 9.09 (s, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.06 (d, J=0.6 Hz, 1H), 7.78 (d,J=2.2 Hz, 1H), 7.33 (s, 1H), 4.81 (s, 2H), 4.18 (t, J=5.5 Hz, 2H), 3.47(s, 3H), 3.40 (d, J=5.0 Hz, 2H), 2.98 (s, 3H), 2.70 (s, 3H). LC-MS:method C, RT=2.10 min, MS (ESI) m/z: 493.10 (M+H)⁺. Analytical HPLCpurity (method B): 100%.

Example 99N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in DMF (1 mL)was added DIEA (0.052 mL, 0.300 mmol) and benzenesulfonyl chloride (6.36mg, 0.036 mmol). The mixture was stirred at room temperature for 15 min.LCMS indicated a completion of the reaction. The reaction was quenchedby water and solvent was removed. The residual was purified viapreparative LC/MS (method D, 55-100% B over 11 min, then a 4-min hold at100% B). Fractions containing the desired product were combined anddried via centrifugal evaporation to give Example 99 (7.0 mg, 0.012mmol, 41.6% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.73 (d,J=1.4 Hz, 1H), 8.00 (s, 2H), 7.85 (d, J=7.2 Hz, 2H), 7.69-7.54 (m, 3H),7.12 (d, J=2.2 Hz, 1H), 4.79 (s, 2H), 4.08 (t, J=5.2 Hz, 2H), 3.47 (s,3H), 3.22 (t, J=5.0 Hz, 2H), 2.67 (s, 3H). LC-MS: method C, RT=2.38 min,MS (ESI) m/z: 555.2 (M+H)⁺. Analytical HPLC purity (method B): 99%.

Example 100N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-2-fluorobenzenesulfonamide

To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in DMF (1 mL)was added DIEA (0.052 mL, 0.300 mmol) and 2-fluorobenzene-1-sulfonylchloride (7.01 mg, 0.036 mmol). The mixture was stirred at roomtemperature for 15 min. LCMS indicated a completion of the reaction. Thereaction was quenched by water and solvent was removed. The residual waspurified via preparative LC/MS (method D, 55-100% B over 10 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 100 (7.6mg, 0.013 mmol, 44.2% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 1H),8.78 (d, J=1.9 Hz, 1H), 8.05 (s, 1H), 7.84 (td, J=7.8, 1.5 Hz, 1H),7.71-7.64 (m, 1H), 7.62 (d, J=2.2 Hz, 1H), 7.45-7.34 (m, 2H), 7.03 (d,J=2.5 Hz, 1H), 4.81 (s, 2H), 4.09 (t, J=5.2 Hz, 2H), 3.47 (s, 3H), 3.36(t, J=5.2 Hz, 2H), 2.69 (s, 3H). LC-MS: method C, RT=2.38 min, MS (ESI)m/z: 573.1 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 101N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide

To a solution of Intermediate 98F (14.52 mg, 0.035 mmol) in DMF (1 mL)was added DIEA (0.061 mL, 0.350 mmol) and 4-fluorobenzene-1-sulfonylchloride (8.17 mg, 0.042 mmol). The mixture was stirred at roomtemperature For 15 min. LCMS indicated a completion of the reaction. Thereaction was quenched by water and solvent was removed. The residual waspurified via preparative LC/MS (method D, 55-100% B over 10 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 101 (11.3mg, 0.020 mmol, 56.3% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 1H),8.78 (d, J=1.7 Hz, 1H), 8.05 (s, 1H), 7.96-7.84 (m, 2H), 7.66 (d, J=2.5Hz, 1H), 7.47-7.37 (m, 2H), 7.14 (d, J=2.2 Hz, 1H), 4.81 (s, 2H), 4.09(t, J=5.2 Hz, 2H), 3.47 (s, 3H), 3.23 (t, J=5.2 Hz, 2H), 2.70 (s, 3H).LC-MS: method C, RT=2.38 min, MS (ESI) m/z: 573.1 (M+H)⁺. AnalyticalHPLC purity (method B): 100%.

Example 102N-(2-(4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-3-fluorobenzenesulfonamide

To a solution of Intermediate 98F (12.45 mg, 0.03 mmol) in DMF (1 mL)was added DIEA (0.052 mL, 0.300 mmol) and 3-fluorobenzene-1-sulfonylchloride (7.01 mg, 0.036 mmol). The mixture was stirred at roomtemperature for 15 min. LCMS indicated a completion of the reaction. Thereaction was quenched by water and solvent was removed. The residual waspurified via preparative LC/MS (method D, 55-100% B over 10 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 102 (7.5mg, 0.013 mmol, 42.8% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 1H),8.78 (d, J=1.9 Hz, 1H), 8.05 (d, J=0.8 Hz, 1H), 7.75-7.59 (m, 4H),7.52-7.42 (m, 1H), 7.13 (d, J=2.5 Hz, 1H), 4.81 (s, 2H), 4.09 (t, J=5.2Hz, 2H), 3.47 (s, 3H), 3.27 (t, J=5.2 Hz, 2H), 2.69 (s, 3H). LC-MS:method C, RT=2.41 min, MS (ESI) m/z: 573.1 (M+H)⁺. Analytical HPLCpurity (method B): 98%.

Example 1036-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carbonitrile

Intermediate 103A: 2-bromo-4-methoxy-1-nitrobenzene

To a solution of 2-bromo-4-fluoro-1-nitrobenzene (2 g, 9.09 mmol) in THF(30 mL) was added sodium methoxide (1.48 g, 27 mmol). The mixture wasstirred at room temperature overnight. Solvent was removed under vacuumand the residual was diluted with EtOAc, quenched with saturatedammonium chloride. The organic layer was washed with saturated sodiumbicarbonate, brine, dried over sodium sulfate and concentrated. Thecrude product was purified with flash chromatography (loading inchloroform, 0% to 50% EtOAc in hexanes over 40 min using a 120 g silicagel cartridge). The desired fractions were combined and concentrated toyield Intermediate 103A (1.7 g, 7.33 mmol, 81% yield) as an off-whitesolid. ¹H NMR (400 MHz, chloroform-d) δ 8.00 (d, J=9.0 Hz, 1H), 7.23 (d,J=2.6 Hz, 1H), 6.93 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s, 3H). LC-MS: methodC, RT=1.82 min, MS (ESI) m/z: 231.9 and 233.9 (M+H)⁺.

Intermediate 103B: 2-bromo-4-methoxyaniline

To a solution of Intermediate 103A (1.7 g, 7.33 mmol) in MeOH (30 mL)was added ammonium chloride (7.84 g, 147 mmol) and zinc dust (4.79 g,73.3 mmol). The mixture was stirred at room temperature for 1 h. LCMSindicated a clean reaction. MeOH was removed. The residue was dilutedwith EtOAc/saturated sodium bicarbonate and stirred at room temperaturefor 10 min. The mixture was filtered to remove insoluble material. Thefiltrate was collected, organic layer was washed with brine, dried oversodium sulfate, concentrated. The crude sample was purified with a 120 gISCO column eluted with 0-100% EtOAc in hexanes for 40 min. The desiredfraction was collected and concentrated to give Intermediate 103B (1.3g, 6.43 mmol, 88% yield) as oil. ¹H NMR (400 MHz, chloroform-d) δ 7.01(d, J=2.0 Hz, 1H), 6.76-6.70 (m, 2H), 3.79 (br. s., 2H), 3.74 (s, 3H).LC-MS: method C, RT=0.80 min, MS (ESI) m/z: 202 and 204 (M+H)⁺.

Intermediate 103C: 4-bromo-6-methoxybenzo[d]thiazol-2-amine

To a mixture of Intermediate 103B (1.3 g, 6.43 mmol) in acetonitrile (15mL) was added ammonium thiocyanate (0.857 g, 11.26 mmol). The mixturewas stirred at room temperature for 10 min. Benzyltrimethylammoniumtribromide (3.39 g, 8.69 mmol) in acetonitrile (10 mL) was addeddropwise (5 min). The mixture was stirred at room temperature overnight.Acetonitrile was removed. The mixture was diluted with EtOAc, saturatedsodium bicarbonate. The insoluble material was removed by filtration.The organic layer of the filtrate was collected, washed with brine,dried over sodium sulfate and concentrated to give Intermediate 103C(1.5 g, 5.79 mmol, 90% yield) as a yellow solid that was used for thenext step without further purification. LC-MS: method C, RT=1.41 min, MS(ESI) m/z: 259 and 261 (M+H)⁺.

Intermediate 103D: tert-butylN-(4-bromo-6-methoxy-1,3-benzothiazol-2-yl)-N-[(tert-butoxy)carbonyl]carbamate

To a solution of Intermediate 103C (1.2 g, 4.63 mmol) in DMF (20 mL) wasadded DMAP (566 mg, 4.63 mmol) and Boc₂O (3032 mg, 13.89 mmol). Themixture was stirred under argon over the weekend. The mixture waspartitioned into water (300 mL) and extracted with ethyl acetate (2×200mL). The organic layers were combined, washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified with a 40 gISCO column eluted with 0-50% EtOAc/hexanes for 40 min. The desiredfraction was collected and concentrated to give Intermediate 103D (400mg, 0.871 mmol, 18.80% yield). LC-MS: method C, RT=2.40 min, MS (ESI)m/z: 302.9 and 304.9 (M+H-Boc)⁺.

Intermediate 103E: 2-amino-6-methoxybenzo[d]thiazole-4-carbonitrile

A mixture of Intermediate 103D (100 mg, 0.218 mmol), zinc cyanide (25.6mg, 0.218 mmol), palladium (II) trifluoroacetate (5.79 mg, 0.017 mmol),racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (13.88 mg, 0.035 mmol)and zinc dust (4.27 mg, 0.065 mmol) in DMA (1.5 mL) was degassed withargon for 5 min. The reaction mixture was heated in a microwave reactorat 100° C. for 20 min. It was diluted with EtOAc/saturated sodiumbicarbonate. The organic layer was washed with brine, dried over sodiumsulfate. After evaporation of solvent, the crude product was purifiedwith a 12 g ISCO column eluted with 0-70% EtOAc in hexanes for 15 min.The desired fraction was collected to give di-boc protected intermediate(50 mg, 0.123 mmol, 56.6% yield) as colorless oil. The intermediate wasredissolved in 1 ml of DCM and TFA (0.839 mL, 10.88 mmol) was added. Themixture was stirred at room temperature for 1 h. LCMS indicated acompletion of the reaction. Solvent was removed and the residual wasdiluted EtOAc/saturated sodium bicarbonate. The organic layer was washedwith brine, dried over sodium sulfate. After evaporation of solvent, thecrude product was purified with a 12 g ISCO column eluted with 0-100%EtOAc in hexanes for 15 min. The desired fraction was collected andconcentrated to give Intermediate 103E (24 mg, 0.117 mmol, 53.7% yield).¹H NMR (400 MHz, methanol-d₄) δ 7.51 (d, J=2.6 Hz, 1H), 7.15 (d, J=2.6Hz, 1H), 3.83 (s, 3H). LC-MS: method C, RT=1.42 min, MS (ESI) m/z: 206(M+H)⁺.

Intermediate 103F: 2-bromo-6-methoxybenzo[d]thiazole-4-carbonitrile

To a stirred solution of copper (II) bromide (20.13 mg, 0.140 mmol) andIntermediate 103E (24 mg, 0.117 mmol) in acetonitrile (2 mL) was addedtert-butyl nitrite (0.020 mL, 0.152 mmol). The mixture was stirred at20° C. for 4.0 h. TLC and LCMS indicated a clean reaction. Acetonitrilewas removed under vacuum, the reaction mixture was diluted with EtOAc,quenched with 1.0 N HCl. The organic layer was collected, washed with0.5 N HCl (2×), saturated sodium bicarbonate, brine, dried over sodiumsulfate. After evaporation of solvent, the crude was purified with a 12g ISCO column eluted with 0-70% EtOAc in hexanes for 20 min.Intermediate 103F (15 mg, 0.056 mmol, 47.7% yield) was obtained as anoff-white solid. ¹H NMR (400 MHz, chloroform-d) δ 7.49 (d, J=2.4 Hz,1H), 7.38 (d, J=2.6 Hz, 1H), 3.92 (s, 3H). LC-MS: method C, RT=1.79 min,MS (ESI) m/z: 268.9 and 270.9 (M+H)⁺.

Example 103

To Intermediate I-2 (9.5 mg, 0.041 mmol), Intermediate 103F (11.02 mg,0.041 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (1.672 mg, 2.047 μmol) was addedtoluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.041 mL, 2M,0.082 mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 120° C. for 40 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layers were collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was purified via preparative LC/MS (method D,45-90% B over 20 min., then a 5-min hold at 100% B). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give Example 103 (1.7 mg, 4.34 μmol, 10.59% yield). ¹HNMR (500 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.82 (s, 1H), 8.16 (br. s., 1H),8.09 (s, 1H), 7.75 (br. s., 1H), 4.82 (s, 2H), 3.93 (s, 3H), 3.48 (s,3H), 2.72 (s, 3H). LC-MS: method C, RT=2.31 min, MS (ESI) m/z: 377.1(M+H)⁺. Analytical HPLC purity (method B): 96%.

Example 104N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

Intermediate 104A: tert-butyl4-bromo-6-methoxybenzo[d]thiazol-2-ylcarbamate

To a solution of Intermediate 103D (300 mg, 0.653 mmol) in DCM (3 mL)was added TFA (0.101 mL, 1.306 mmol) and the mixture was stirred at roomtemperature overnight. The mixture was diluted with EtOAc and saturatedNaHCO₃, extracted with EtOAc. The combined organic layer was washed withbrine, dried with MgSO₄ and concentrated to give Intermediate 104A (235mg, 0.654 mmol, 100% yield) as an off white solid which was used fornext step without further purification. ¹H NMR (400 MHz, chloroform-d) δ7.24-7.20 (m, 2H), 3.86 (s, 3H), 1.56 (s, 9H). LC-MS: method C, RT=2.30min, MS (ESI) m/z: 359 and 360.9 (M+H)⁺.

Intermediate 104B: tert-butyl4-cyclopropyl-6-methoxybenzo[d]thiazol-2-ylcarbamate

A solution of Intermediate 104A (30 mg, 0.084 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (6.82 mg, 8.35 μmol) in THF (1 mL) wasdegassed for 2 min. To this solution was added cyclopropylzinc(II)bromide (0.835 mL, 0.5 M in THF, 0.418 mmol). The reaction tube wassealed and heated at 65° C. for 1 h. LCMS indicated a completion of thereaction. The reaction mixture was diluted with EtOAc/water. The organicphase was washed with brine, dried over sodium sulfate. The cruderesidue was purified with a 12 g ISCO column eluted with 0-70% EtOAc inhexanes for 15 min. Intermediate 104B (26 mg, 0.081 mmol, 97% yield) wasobtained as colorless oil. LC-MS: method C, RT=2.33 min, MS (ESI) m/z:321 (M+H)⁺.

Intermediate 104C: 4-cyclopropyl-6-methoxybenzo[d]thiazol-2-amine

To a solution of Intermediate 104B (125 mg, 0.390 mmol) in DCM (1 mL)was added TFA (3.01 mL, 39.0 mmol). The mixture was stirred at roomtemperature for 1 h. Solvent was removed under vacuum and the residualwas diluted with EtOAc and saturated NaHCO₃, extracted with EtOAc. Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated to give Intermediate 104C (80 mg, 0.363 mmol, 93% yield) asan off-white solid. ¹H NMR (400 MHz, chloroform-d) δ 6.94 (d, J=2.4 Hz,1H), 6.41 (d, J=2.4 Hz, 1H), 5.19 (br. s., 2H), 3.80 (s, 3H), 2.57-2.43(m, 1H), 1.14-0.99 (m, 2H), 0.86-0.74 (m, 2H). LC-MS: method C, RT=1.46min, MS (ESI) m/z: 221 (M+H)⁺.

Intermediate 104D: 2-bromo-4-cyclopropyl-6-methoxybenzo[d]thiazole

To a stirred solution of copper (II) bromide (188 mg, 1.307 mmol) andIntermediate 104C (240 mg, 1.089 mmol) in acetonitrile (3 mL) was addedtert-butyl nitrite (0.187 mL, 1.416 mmol). The mixture was stirred atroom temperature overnight. Acetonitrile was removed, the reactionmixture was diluted with EtOAc, quenched with 1.0 N HCl. The organiclayer was collected, washed with 0.5 N HCl (2×), saturated sodiumbicarbonate, brine, dried over sodium sulfate. After evaporation ofsolvent, the crude oil was purified with a 40 g ISCO column eluted with0-70% EtOAc in hexanes for 20 min. The desired fraction was collectedand concentrated to give Intermediate 104D (180 mg, 0.633 mmol, 58.1%yield) as yellow oil. ¹H NMR (400 MHz, chloroform-d) δ 7.03 (d, J=2.4Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 3.83 (s, 3H), 2.73 (s, 1H), 1.20-1.06(m, 2H), 0.93-0.81 (m, 2H). LC-MS: method C, RT=2.26 min, MS (ESI) m/z:283.9 and 285.9. (M+H)⁺.

Intermediate 104E: 2-bromo-4-cyclopropylbenzo[d]thiazol-6-ol

To a solution of Intermediate 104D (150 mg, 0.528 mmol) in DCM (3 mL)was added boron tribromide (1.056 mL, 1.0 M in DCM, 1.056 mmol) at roomtemperature. The mixture was stirred at room temperature for 1 h. Themixture was diluted with EtOAc, quenched with ice and saturated NaHCO₃,extracted with EtOAc. The combined organic layer was washed with brine,dried with MgSO₄ and concentrated. The crude was purified with a 12 gISCO column eluted with 0-100% EtOAc in hexanes for 20 min. The desiredfraction was collected to give Intermediate 104E (100 mg, 0.37 mmol,70.2% yield) as a white solid. ¹H NMR (400 MHz, Methanol-d₄) δ 7.02 (d,J=2.4 Hz, 1H), 6.45 (d, J=2.2 Hz, 1H), 2.60 (tt, J=8.5, 5.2 Hz, 1H),1.14-1.03 (m, 2H), 0.90-0.78 (m, 2H). LC-MS: method C, RT=2.01 min, MS(ESI) m/z: 269.9 and 271.9 (M+H)⁺.

Intermediate 104F: tert-butyl2-(2-bromo-4-cyclopropylbenzo[d]thiazol-6-yloxy) ethylcarbamate

A solution of DIAD (0.108 mL, 0.555 mmol) in toluene (1 ml) was addeddropwise to a mixture of Intermediate 104E (50 mg, 0.185 mmol),tert-butyl (2-hydroxyethyl)carbamate (35.8 mg, 0.222 mmol) andtriphenylphosphine (97 mg, 0.370 mmol) in toluene (1 mL) at 110° C. Themixture was stirred at 110° C. for 30 min. LCMS indicated a completionof the reaction. The mixture was concentrated and purified with a 12 gISCO column eluted with 0-70% EtOAc in hexanes for 20 min. The desiredfraction was collected and concentrated to give Intermediate 104F (70mg, 0.169 mmol, 92% yield). ¹H NMR (400 MHz, chloroform-d) δ 7.02 (d,J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.03 (t, J=5.2 Hz, 2H), 3.55 (q,J=5.2 Hz, 2H), 2.80-2.65 (m, 1H), 1.48-1.42 (m, 9H), 1.16-1.08 (m, 2H),0.91-0.82 (m, 2H). LC-MS: method C, RT=2.35 min, MS (ESI) m/z: 412.9 and414.9 (M+H)⁺.

Intermediate 104G: tert-butyl2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethylcarbamate

To Intermediate I-2 (35 mg, 0.151 mmol), Intermediate 104F (62.3 mg,0.151 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (6.16 mg, 2M, 7.54 μmol) wasadded toluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.151 mL,0.302 mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 120° C. for 40 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layers were collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 12 g ISCO column which was eluted with hexanes for 3min., then a 20 min gradient from 0% to 100% EtOAc in hexanes Thedesired fractions were combined and concentrated to give Intermediate104G (70 mg, 0.108 mmol, 71.3% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.09(s, 1H), 8.82 (s, 1H), 8.02 (s, 1H), 7.49 (br. s., 1H), 7.02 (br. s.,1H), 6.58 (br. s., 1H), 4.81 (s, 2H), 4.04 (br. s., 2H), 3.47 (s, 3H),3.33 (m., 2H), 3.01-2.88 (m, 1H), 2.69 (s, 3H), 1.39 (s, 9H), 1.17 (d,J=7.4 Hz, 2H), 1.00 (br. s., 2H). LC-MS: method C, RT=2.50 min, MS (ESI)m/z: 521 (M+H)⁺.

Intermediate 104H:

2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethanamine

To a solution of Intermediate 104G (65 mg, 0.125 mmol) in DCM (1 mL) wasadded 2,6-lutidine (43.6 μl, 0.375 mmol) followed by TMS-OTf (90 μl,0.499 mmol) at room temperature. The mixture was stirred at roomtemperature for 1 h. The mixture was diluted with EtOAc and NaHCO₃,extracted with EtOAc. The combined organic layer was washed with brine,dried with MgSO₄ and concentrated to give Intermediate 104H (52.5 mg,0.125 mmol, 100% yield). LC-MS: method C, RT=2.01 min, MS (ESI) m/z: 421(M+H)⁺.

Example 104

To a solution of Intermediate 104H (14 mg, 0.033 mmol) in DMF (1 mL) wasadded DIEA (0.058 mL, 0.333 mmol) and benzenesulfonyl chloride (5.15 μl,0.040 mmol). The mixture was stirred at room temperature for 30 min.LCMS indicated a completion of the reaction. The reaction was quenchedwith 0.2 ml of MeOH. Solvent was removed. The residual was purified viapreparative LC/MS (method D, 50-90% B over 20 min., then a 5-min hold at100% B). Fractions containing the desired product were combined anddried via centrifugal evaporation to give Example 104 (4.8 mg, 8.56μmol, 25.7% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.80 (s,1H), 8.01 (s, 1H), 7.95 (br. s., 1H), 7.85 (d, J=7.2 Hz, 2H), 7.68-7.57(m, 3H), 7.40 (s, 1H), 6.45 (s, 1H), 4.80 (s, 2H), 4.04 (br. s., 2H),3.47 (s, 3H), 3.19 (br. s., 2H), 2.93 (br. s., 1H), 2.68 (s, 3H), 1.17(d, J=8.0 Hz, 2H), 0.97 (d, J=3.3 Hz, 2H). LC-MS: method C, RT=2.53 min,MS (ESI) m/z: 561.20 (M+H)⁺. Analytical HPLC purity (method B): 100%

Example 105N-(2-(4-cyclopropyl-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide

To a solution of Intermediate 104H (16 mg, 0.038 mmol) in DMF (1 mL) wasadded DIEA (0.066 mL, 0.380 mmol) and 4-fluorobenzene-1-sulfonylchloride (8.89 mg, 0.046 mmol). The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of the reaction. Thereaction was quenched with 0.2 ml of MeOH. Solvent was removed, theresidual was purified via preparative LC/MS (method D, 50-90% B over 20min., then a 5-min hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to giveExample 105 (8.4 mg, 0.015 mmol, 38.2% yield). ¹H NMR (500 MHz, DMSO-d₆)δ 9.08 (s, 1H), 8.81 (s, 1H), 8.02 (br. s., 2H), 7.92-7.86 (m, 2H),7.49-7.37 (m, 3H), 6.44 (s, 1H), 4.81 (s, 2H), 4.04 (br. s., 2H), 3.47(s, 3H), 3.21 (br. s., 2H), 2.92 (d, J=5.2 Hz, 1H), 2.70-2.66 (m, 3H),1.17 (d, J=7.4 Hz, 2H), 0.97 (d, J=2.5 Hz, 2H). LC-MS: method C, RT=2.54min, MS (ESI) m/z: 579.20 (M+H)⁺. Analytical HPLC purity (method B):100%.

Example 106N-(2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

Intermediate 106A: 2-chlorobenzo[d]thiazol-6-ol

Aluminum chloride (7.01 g, 52.6 mmol) was added to a solution of2-chloro-6-methoxybenzo[d]thiazole (3.5 g, 17.53 mmol) in toluene (80mL). The mixture was heated at 110° C. for 1.5 h. TLC indicated acomplete conversion of starting material. The reaction mixture wascooled to room temperature, quenched with ice-cold 1.0 N HCl (50 mL),stirred at room temperature for 30 min. The precipitate was collected byfiltration, washed with water (3×), saturated sodium bicarbonate (3×),water (3×) and air-dried for 1.0 h under vacuum. It was further driedunder high vacuum overnight to give Intermediate 106A (2.9 g, 15.62mmol, 89% yield) as a pale gray solid. The crude sample was used for thenext step without purification. ¹H NMR (400 MHz, methanol-d₄) δ 7.70 (d,J=8.8 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H).LC-MS: method C, RT=1.65 min, MS (ESI) m/z: 185.8 (M+H)⁺.

Intermediate 106B: tert-butyl2-(2-chlorobenzo[d]thiazol-6-yloxy)ethylcarbamate

A solution of DIAD (0.943 mL, 4.85 mmol) in toluene (4 mL) was addeddropwise to a mixture of Intermediate 106A (300 mg, 1.616 mmol),tert-butyl (2-hydroxyethyl)carbamate (313 mg, 1.939 mmol) andtriphenylphosphine (848 mg, 3.23 mmol) in toluene (10 mL) at 110° C. Themixture turned to a clean solution and was stirred at 110° C. for 30min. LCMS indicated a completion of the reaction. The mixture wasconcentrated and purified with a 40 g ISCO column eluted with 0-70%EtOAc in hexanes for 20 min. The desired fraction was collected andconcentrated to give Intermediate 106B (620 mg, 1.508 mmol, 93% yield).¹H NMR (400 MHz, chloroform-d) δ 7.83 (d, J=9.0 Hz, 1H), 7.23 (d, J=2.4Hz, 1H), 7.07 (dd, J=8.9, 2.5 Hz, 1H), 5.12-4.94 (m, 2H), 4.11-4.05 (m,2H), 3.57 (q, J=5.1 Hz, 2H), 1.51-1.42 (m, 9H). LC-MS: method C, RT=2.49min, MS (ESI) m/z: 329 (M+H)⁺.

Intermediate 106C: tert-butyl2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethylcarbamate

To Intermediate I-2 (35 mg, 0.151 mmol), Intermediate 106B (62.0 mg,0.151 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (6.16 mg, 7.54 μmol) was addedtoluene (0.75 mL), EtOH (0.25 mL) and sodium carbonate (0.151 mL, 2M,0.302 mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 120° C. for 30 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layers were collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 40 g ISCO column which was eluted with hexanes for 3min., then a 20 min gradient from 0% to 100% EtOAc in hexanes. Thedesired fractions were combined and concentrated to give Intermediate106C (63 mg, 0.119 mmol, 79% yield) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.09 (br. s., 1H), 8.80 (br. s., 1H), 8.05-7.99 (m, 2H), 7.74(br. s., 1H), 7.16 (d, J=8.8 Hz, 1H), 7.05 (br. s., 1H), 4.81 (br. s.,2H), 4.08 (br. s., 2H), 3.47 (br. s., 3H), 3.36 (br. s., 2H), 2.68 (br.s., 3H), 1.39 (br. s., 9H). LC-MS: method C, RT=2.40 min, MS (ESI) m/z:481 (M+H)⁺.

Intermediate 106D2-(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethanamine

To a mixture of Intermediate 106C (60 mg, 0.125 mmol) in DCM (2 ml) wasadded 2,6-lutidine (43.6 μl, 0.375 mmol) followed by TMS-OTf (90 μl,0.499 mmol). The mixture was stirred at room temperature for 1 h. LCMSindicated a completion of the reaction. The mixture was diluted withEtOAc and NaHCO₃, extracted with EtOAc. The combined organic layer waswashed with brine, dried with MgSO₄ and concentrated to giveIntermediate 106D (45 mg, 0.118 mmol, 95% yield). ¹H NMR (400 MHz,chloroform-d) δ 9.09 (s, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.04 (d, J=8.8 Hz,1H), 7.95 (s, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.15 (dd, J=9.0, 2.4 Hz, 1H),4.85 (s, 2H), 4.11 (t, J=4.8 Hz, 2H), 3.58 (s, 3H), 3.17 (br. s., 2H),2.70 (s, 3H). LC-MS: method C, RT=1.74 min, MS (ESI) m/z: 381 (M+H)⁺.

Example 106

To a solution of Intermediate 106D (14 mg, 0.037 mmol) in DMF (1 mL) wasadded DIEA (0.064 mL, 0.368 mmol) and benzenesulfonyl chloride (5.69 μl,0.044 mmol). The mixture was stirred at room temperature for 30 min.LCMS indicated a completion of the reaction. The reaction mixture wasquenched with 0.2 ml of MeOH. Solvent was removed, the residual waspurified via preparative LC/MS (method D, 40-80% B over 10 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 106 (10.7mg, 0.021 mmol, 55.9% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (br. s.,1H), 8.79 (br. s., 1H), 8.12-7.94 (m, 3H), 7.85 (d, J=6.9 Hz, 2H),7.69-7.53 (m, 4H), 7.08 (d, J=8.5 Hz, 1H), 4.81 (br. s., 2H), 4.08 (br.s., 2H), 3.47 (br. s., 3H), 3.22 (br. s., 2H), 2.68 (br. s., 3H). LC-MS:method C, RT=2.25 min, MS (ESI) m/z: 521.15 (M+H)⁺. Analytical HPLCpurity (method B): 100%.

Example 107 4-fluoro N (2 (2 (2(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

To a solution of Intermediate 106D (16 mg, 0.042 mmol) in DMF (1 mL) wasadded DIEA (0.073 mL, 0.421 mmol) and 4-fluorobenzene-1-sulfonylchloride (9.82 mg, 0.050 mmol). The mixture was stirred at roomtemperature for 30 min. LCMS indicated a completion of the reaction. Thereaction mixture was quenched with 0.2 ml of MeOH. Solvent was removed,the residual was purified via preparative LC/MS (method D, 40-80% B over10 min., then a 5-min hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to giveExample 107 (16.3 mg, 0.030 mmol, 70.5% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 9.09 (br. s., 1H), 8.79 (br. s., 1H), 8.09-7.97 (m, 3H), 7.90(br. s., 2H), 7.66 (br. s., 1H), 7.42 (t, J=8.4 Hz, 2H), 7.07 (d, J=9.1Hz, 1H), 4.81 (br. s., 2H), 4.08 (br. s., 2H), 3.47 (m, 3H), 3.23 (br.s., 2H), 2.68 (br. s., 3H). LC-MS: method C, RT=2.25 min, MS (ESI) m/z:539.15 (M+H)⁺. Analytical HPLC purity (method B): 98%.

Example 108 4-fluoro N (2 (2 (2 (1fluoroethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

Intermediate 108A: 1-(5-bromo-7-methylquinoxalin-2-yl)ethanone

To a suspension of methyl 5-bromo-7-methylquinoxaline-2-carboxylate (300mg, 1.067 mmol) in toluene (5 mL) was addedN₁,N₂-dimethylethane-1,2-diamine (DMEDA) (0.126 mL, 1.174 mmol) andtrimethylaluminum (1.601 mL, 3.20 mmol) dropwise under argon at roomtemperature. The mixture was stirred at room temperature over theweekend. The mixture was diluted with EtOAc and water, extracted withEtOAc. The combined organic layer was washed with saturated NaHCO₃ andbrine, dried with MgSO₄ and concentrated. The crude sample was purifiedwith a 40 g ISCO column eluted with 0-80% EtOAc in hexanes for 20 min.The desired fraction was collected to give Intermediate 108A (250 mg,0.943 mmol, 88% yield) as a yellow solid. ¹H NMR (400 MHz, chloroform-d)δ 9.50 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 7.96 (dd, J=1.7, 1.0 Hz, 1H),2.85 (s, 3H), 2.63 (s, 3H). LC-MS: method C, RT=1.99 min, MS (ESI) m/z:265 and 267 (M+H)⁺.

Intermediate 108B: 2-acetyl-7-methylquinoxalin-5-ylboronic acid

A mixture of Intermediate 108A (80 mg, 0.302 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (123 mg,0.483 mmol), potassium acetate (59.2 mg, 0.604 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (9.86 mg, 0.012 mmol) in dioxane (1 ml) wasdegassed with argon for 10 min. The reaction mixture was heated in amicrowave reactor at 130° C. for 30 min. The mixture was diluted withEtOAc/water, insoluble material was removed by filtration. The filtratewas extracted with EtOAc, washed with brine, dried over sodium sulfate,concentrated to give Intermediate 108B (69.0 mg, 0.3 mmol) which wasused for next step without purification. LC-MS: method C, RT=1.94 min,MS (ESI) m/z: 231 (M+H)⁺ (boronic acid).

Intermediate 108C:N-(2-(2-(2-acetyl-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide

To Intermediate 108B (69.0 mg, 0.3 mmol), Intermediate I-5 (111 mg,0.250 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (10.21 mg, 0.013 mmol) was addedtoluene (1.5 mL), EtOH (0.5 mL) and sodium carbonate (0.250 mL, 2M,0.500 mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 130° C. for 30 min. To thereaction mixture was added EtOAc/water/brine. The insoluble was removedby filtration with a pad of celite. The organic layers were collected,washed with brine, dried over sodium sulfate. After evaporation ofsolvent, the crude product was dissolved in a small amount of chloroformand charged to a 12 g ISCO column which was eluted with hexanes for 3min., then a 15 min gradient from 0% to 100% EtOAc in hexanes. Thedesired fractions were combined and concentrated to give Intermediate108C (20 mg, 0.036 mmol, 14.53% yield) as a yellow solid. ¹H NMR (400MHz, chloroform-d) δ 9.57 (s, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.08 (dd,J=2.0, 0.9 Hz, 1H), 7.97-7.90 (m, 2H), 7.24-7.16 (m, 3H), 6.85 (d, J=1.5Hz, 1H), 5.04-4.90 (m, 1H), 4.15-4.09 (m, 2H), 3.48-3.40 (m, 2H), 2.88(s, 3H), 2.83 (s, 3H), 2.77 (s, 3H). LC-MS: method C, RT=2.50 min, MS(ESI) m/z: 551 (M+H)⁺.

Intermediate 108D 4-fluoro N (2 (2 (2 (1hydroxyethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

To a solution of Intermediate 108C (20 mg, 0.036 mmol) in MeOH (1.5 ml)and THF (0.5 mL) was added CeCl₃ (13.53 mg, 0.036 mmol) and NaBH₄ (5.50mg, 0.145 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1h. TLC and LCMS indicated a completion of the reaction. The reactionmixture was diluted with saturated NH₄Cl solution and EtOAc. Thecombined organic layer was washed with brine, dried with sodium sulfate,and concentrated under reduced pressure to give Intermediate 108D (20mg, 0.036 mmol, 100% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (br. s.,1H), 8.78 (br. s., 1H), 8.06 (br. s., 1H), 8.02-7.94 (m, 1H), 7.90 (br.s., 2H), 7.45 (d, J=16.8 Hz, 3H), 6.86 (br. s., 1H), 5.86 (br. s., 1H),5.03 (br. s., 1H), 4.05 (d, J=3.0 Hz, 2H), 3.21 (d, J=3.0 Hz, 2H), 2.73(br. s., 3H), 2.68 (br. s., 3H). LC-MS: method C, RT=2.33 min, MS (ESI)m/z: 553 (M+H)⁺.

Example 108

To a solution of Intermediate 108D (15 mg, 0.027 mmol) in DCM (1 ml) wasadded diethylaminosulfur trifluoride (7.17 μl, 0.054 mmol) dropwise at−78° C. The mixture was stirred from −78° C. to room temperature for 30min. LCMS indicated a completion of the reaction. The reaction wasquenched with water, extracted with EtOAc, the combined organic layerwas washed with NaHCO₃, brine and concentrated. The crude sample waspurified via preparative LC/MS (method D, 50-90% B over 20 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 108 (5.3mg, 9.46 μmol, 34.9% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (br. s.,1H), 8.83 (br. s., 1H), 8.06 (br. s., 2H), 7.90 (br. s., 2H), 7.44 (d,J=13.5 Hz, 3H), 6.86 (br. s., 1H), 6.19-5.98 (m, 1H), 4.05 (br. s., 2H),3.22 (br. s., 2H), 2.73 (br. s., 3H), 2.69 (br. s., 3H), 1.85-1.75 (m,3H). LC-MS: method C, RT=2.70 min, MS (ESI) m/z: 555.10 (M+H)⁺.Analytical HPLC purity (method B): 99%.

Example 109N-(2-(4-cyano-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide

Intermediate 109A: tert-butyl2-(4-cyano-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethylcarbamate

A mixture of Intermediate 98E (60 mg, 0.116 mmol), zinc cyanide (27.36mg, 0.232 mmol), palladium (II) trifluoroacetate (6.20 mg, 18.64 μmol),racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (14.86 mg, 0.019 mmol)and zinc dust (4.57 mg, 0.070 mmol) in DMA (2 mL) was degassed withargon for 5 min. The reaction mixture was heated in a microwave reactorat 130° C. for 1 h. The mixture was diluted with EtOAc/saturated sodiumbicarbonate. The organic layer was washed with brine, dried over sodiumsulfate. After evaporation of solvent, the crude product was purifiedwith a 40 g ISCO column eluted with 0-100% EtOAc in hexanes for 20 min.The desired fraction was collected and concentrated to give Intermediate109A (10 mg, 0.020 mmol, 16.98% yield). ¹H NMR (400 MHz, chloroform-d) δ9.09 (s, 1H), 9.04 (d, J=2.0 Hz, 1H), 7.95 (s, 1H), 7.66 (dd, J=4.2, 2.4Hz, 1H), 7.43 (t, J=2.3 Hz, 1H), 4.86 (s, 2H), 4.19-4.14 (m, 2H), 3.62(d, J=5.5 Hz, 2H), 3.59 (s, 3H), 2.73 (s, 3H), 1.48 (s, 9H). LC-MS:method C, RT=2.54 min, MS (ESI) m/z: 506 (M+H)⁺.

Intermediate 109B6-(2-aminoethoxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carbonitrile

To a mixture of Intermediate 109A (10 mg, 0.020 mmol) in DCM (1 mL) wasadded 2,6-lutidine (6.91 μl, 0.059 mmol) followed by TMS-OTf (14.30 μl,0.079 mmol) at room temperature. The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of the reaction. Themixture was diluted with EtOAc and saturated NaHCO₃, extracted withEtOAc. The combined organic layer was washed with brine, dried withMgSO₄ and concentrated to give Intermediate 109B which was used for nextstep without purification. LC-MS: method C, RT=1.83 min, MS (ESI) m/z:406 (M+H)⁺.

Example 109

To a solution of Intermediate 109B in DMF (1 mL) was added DIEA (0.034mL, 0.197 mmol) and 4-fluorobenzene-1-sulfonyl chloride (4.61 mg, 0.024mmol). The mixture was stirred at room temperature for 30 min. LCMSindicated a completion of the reaction. The reaction was quenched with0.2 ml of MeOH. Solvent was removed, the residual was purified viapreparative LC/MS (method D, 45-85% B over 18 min., then a 5-min hold at100% B). Fractions containing the desired product were combined anddried via centrifugal evaporation to give Example 109 (0.7 mg, 0.621μmol, 3.15% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.76 (d,J=1.7 Hz, 1H), 8.06 (d, J=2.5 Hz, 1H), 8.03 (d, J=0.5 Hz, 1H), 7.89 (dd,J=8.8, 5.2 Hz, 2H), 7.59 (dd, J=3.2, 2.6 Hz, 1H), 7.41 (t, J=8.8 Hz,2H), 4.82 (s, 2H), 4.13 (td, J=5.1, 2.5 Hz, 2H), 3.47 (s, 3H), 3.24 (t,J=5.2 Hz, 2H), 2.78 (s, 3H). LC-MS: method C, RT=2.20 min, MS (ESI) m/z:564.20 (M+H)⁺. Analytical HPLC purity (method B): 97%.

Example 1102-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylphenylcarbamate

Intermediate 110A2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylacetate

To a solution of Intermediate 35B (125 mg, 0.370 mmol) in DMF (4 mL) wasadded cesium carbonate (362 mg, 1.111 mmol), then 2-bromoethyl acetate(0.049 mL, 0.445 mmol) was added dropwise. The reaction mixture wasstirred at room temperature overnight. LCMS indicated a completion ofthe reaction. The reaction mixture was diluted with EtOAc and water,extracted with EtOAc, the combined organic layer was washed with brine,dried with MgSO₄ and concentrated. The crude sample was purified with a12 g ISCO column, eluted with 0-100% EtOAc in hexane for 15 min. Thedesired fraction was collected and concentrated to give Intermediate110A (150 mg, 0.354 mmol, 96% yield) as a yellow solid. ¹H NMR (400 MHz,chloroform-d) δ 8.65 (d, J=1.5 Hz, 1H), 8.54 (s, 1H), 7.73 (dd, J=1.8,0.9 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.95 (dd, J=2.4, 0.9 Hz, 1H),4.53-4.43 (m, 2H), 4.30-4.21 (m, 2H), 4.12 (s, 3H), 2.19-2.09 (m, 3H).LC-MS: method C, RT=2.58 min, MS (ESI) m/z: 424 (M+H)⁺.

Intermediate 110B2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethanol

To a suspension of Intermediate 110A (190 mg, 0.449 mmol) in THF (3 mL)and MeOH (1 mL) was added 1 N NaOH (1.346 mL, 1.346 mmol) at roomtemperature. The mixture was stirred at room temperature for 1 h. LCMSindicated a completion of the reaction. The mixture was diluted withEtOAc and 1N HCl, extracted with EtOAc, the combined organic layer waswashed with water and brine, dried with MgSO₄ and concentrated toIntermediate 110B (155 mg, 0.394 mmol, 88% yield) as a yellow solid. ¹HNMR (500 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.56 (s, 1H), 7.78 (s, 1H), 7.50(s, 1H), 6.99 (s, 1H), 4.91 (br. s., 1H), 4.07 (m, 5H), 3.76 (d, J=4.1Hz, 2H), 2.73 (s, 3H), 2.62 (s, 3H). LC-MS: method C, RT=2.41 min, MS(ESI) m/z: 382 (M+H)⁺.

Intermediate 110C2-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbonochloridate

To a solution of Intermediate 110B (150 mg, 0.393 mmol) in THF (5 mL) atroom temperature was added 15% phosgene in toluene (1.387 mL, 1.966mmol), and the mixture was stirred at room temperature for 5 h. LCMSindicated the reaction was complete. Solvent was removed and the samplewas dried under vacuum overnight to give Intermediate 110C (175 mg,0.394 mmol, 100% yield) as a yellow solid. It was used for the next stepwithout any purification. LC-MS: method C, RT=2.73 min, MS (ESI) m/z:444 (M+H)⁺.

Example 110

To a solution of Intermediate 110C (20 mg, 0.045 mmol) in DCM (1 mL) andTHF (0.5 mL) was added aniline (14.69 mg, 0.158 mmol), followed by DIEA(0.079 mL, 0.451 mmol). The mixture was stirred at room temperature for0.5 h. LCMS indicated a completion of reaction. The reaction mixture wasquenched by addition of a small amount of MeOH/water/0.1% TFA (HPLCsolvent) and diluted with EtOAc and water, extracted with EtOAc. Thecombined organic layer was washed with brine, dried over MgSO₄ andconcentrated. The crude sample was purified via preparative LC/MS(method D, 70-100% B over 10 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to give Example 110 (8.6 mg, 0.017 mmol, 37.8%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.79 (br. s., 1H), 8.71 (s, 1H),8.57 (s, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.27(t, J=7.6 Hz, 2H), 7.03 (s, 1H), 6.99 (t, J=7.4 Hz, 1H), 4.47 (br. s.,2H), 4.33 (br. s., 2H), 4.07 (s, 3H), 2.74 (s, 3H), 2.63 (s, 3H). LC-MS:method C, RT=2.80 min, MS (ESI) m/z: 501.20 (M+H)⁺. Analytical HPLCpurity (method B): 99%.

Example 1112-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylpyridin-3-ylcarbamate

To a solution of Intermediate 110C (20 mg, 0.045 mmol) in DCM (1 mL) andTHF (0.5 mL) was added pyridin-3-amine (14.84 mg, 0.158 mmol) followedby DIEA (0.079 mL, 0.451 mmol). The mixture was stirred at roomtemperature overnight. The reaction was quenched by addition of a smallamount of MeOH/water/0.1% TFA (HPLC solvent). Solvent was removed undervacuum. The crude was purified via preparative LC/MS (method D, 55-100%B over 10 min., then a 5-min hold at 100% B). Fractions containing thedesired product were combined and dried via centrifugal evaporation togive Example 111 (4.1 mg, 8.17 μmol, 18.14% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 10.05 (br. s., 1H), 8.65 (br. s., 1H), 8.58 (s, 1H), 8.22 (d,J=3.6 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.57 (s, 1H),7.42-7.29 (m, 1H), 7.03 (s, 1H), 4.50 (br. s., 2H), 4.34 (br. s., 2H),4.08 (s, 3H), 2.78-2.69 (m, 3H), 2.63 (s, 3H). LC-MS: method C, RT=2.09min, MS (ESI) m/z: 502.10 (M+H)⁺. Analytical HPLC purity (method B):100%.

Example 1122-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl6-methoxypyridin-3-ylcarbamate

To a solution of Intermediate 110C (20 mg, 0.045 mmol) in DCM (1 mL) andTHF (0.5 mL) was added 6-methoxypyridin-3-amine (19.58 mg, 0.158 mmol)followed by DIEA (0.079 mL, 0.451 mmol). The mixture was stirred at roomtemperature for 0.5 h. LCMS indicated a completion of reaction. Thereaction was quenched by addition of a small amount of MeOH/water/0.1%TFA (HPLC solvent). Solvent was removed under vacuum. The crude samplewas purified via preparative LC/MS (method D, 70-100% B over 10 min.,then a 5-min hold at 100% B). Fractions containing the desired productwere combined and dried via centrifugal evaporation to give Example 112(8.6 mg, 0.016 mmol, 35.2% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.77 (br.s., 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.24 (br. s., 1H), 7.81 (s, 1H),7.78 (d, J=7.7 Hz, 1H), 7.57 (s, 1H), 7.03 (s, 1H), 6.78 (d, J=8.8 Hz,1H), 4.47 (br. s., 2H), 4.33 (br. s., 2H), 4.08 (s, 3H), 3.80 (s, 3H),2.75 (s, 3H), 2.64 (s, 3H). LC-MS: method C, RT=2.52 min, MS (ESI) m/z:532.25 (M+H)⁺. Analytical HPLC purity (method B): 98%.

Example 1132-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylpyridin-4-ylcarbamate

To a solution of Intermediate 110C (20 mg, 0.045 mmol) in DCM (1 mL) andTHF (0.5 mL) was added pyridin-4-amine (14.84 mg, 0.158 mmol) followedby DIEA (0.079 mL, 0.451 mmol). The mixture was stirred at roomtemperature overnight. The reaction was quenched by addition of a smallamount of MeOH/water/0.1% TFA (HPLC solvent). The reaction mixture wasdiluted with EtOAc and water, extracted with EtOAc. The combined organiclayer was washed with brine, dried with MgSO₄ and concentrated. Thecrude sample was purified via preparative LC/MS (method D, 55-95% B over15 min., then a 6-min hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to giveExample 113 (2.6 mg, 4.98 μmol, 11.05% yield). ¹H NMR (500 MHz, DMSO-d₆)δ 10.29 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.38 (d, J=4.7 Hz, 2H),7.82 (s, 1H), 7.57 (s, 1H), 7.45 (d, J=5.0 Hz, 2H), 7.04 (s, 1H), 4.51(br. s., 2H), 4.35 (br. s., 2H), 4.08 (s, 3H), 2.75 (s, 3H), 2.64 (s,3H). LC-MS: method C, RT=2.11 min, MS (ESI) m/z: 502.15 (M+H)⁺.Analytical HPLC purity (method B): 96%.

Example 114N-(2-(2-(2-((difluoromethoxy)methyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)-4-fluorobenzenesulfonamide

Intermediate 114A: methyl7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline-2-carboxylate

A mixture of methyl 5-bromo-7-methylquinoxaline-2-carboxylate (225 mg,0.800 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(447 mg, 1.761 mmol), potassium acetate (196 mg, 2.001 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (26.1 mg, 0.032 mmol) in dioxane (3.0 mL) wasdegassed with argon for 10 min. The reaction mixture was heated in amicrowave reactor at 120° C. for 30 min. LCMS indicated a completeconversion of starting material. The mixture was diluted withEtOAc/water, insoluble material was removed by filtration. The filtratewas extracted with EtOAc, washed with brine, dried over sodium sulfate.The crude product was purified with flash chromatography (loading inchloroform, 5% to 75% EtOAc in hexanes over 12 min using a 12 g silicagel cartridge). The desired fractions were combined and concentrated toyield Intermediate 114A (225 mg, 0.686 mmol, 86% yield) as brown solid.LC-MS: method C, RT=1.48 min, MS (ESI) m/z: 247 (M+H)⁺ (boronic acid).

Intermediate 114B: ethyl5-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate

To Intermediate 114A (89 mg, 0.271 mmol), Intermediate I-5 (115 mg,0.258 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (10.54 mg, 0.013 mmol) was addedtoluene (3 mL), EtOH (1 mL) and sodium carbonate (0.258 mL, 2M, 0.516mmol). The mixture was degassed with argon for 5 min. The reactionmixture was heated in a microwave reactor at 130° C. for 30 min. Themixture was diluted with EtOAc and water, extracted with EtOAc. Thecombined organic layer was washed with brine, dried with MgSO₄ andconcentrated. The crude sample was purified with a 12 g ISCO columneluted with EtOAc in hexanes for 15 min. The desired fraction wascollected and concentrated to give Intermediate 114B (45 mg, 0.039 mmol,15.01% yield) as a yellow solid [Note: Transesterification with the EtOHsolvent occurred under these reaction conditions]. ¹H NMR (400 MHz,chloroform-d) δ 9.62 (s, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.84 (s, 1H), 8.17(dd, J=1.8, 0.9 Hz, 1H), 8.00-7.76 (m, 2H), 7.23-7.07 (m, 2H), 6.84 (dd,J=2.4, 0.9 Hz 1H), 4.63 (q, J=7.3 Hz, 2H), 4.12-4.03 (m, 2H), 3.48-3.39(m, 2H), 1.93 (s, 3H), 1.59 (s, 3H), 1.54 (t, J=7.2 Hz, 3H). LC-MS:method C, RT=2.44 min, MS (ESI) m/z: 581 (M+H)⁺.

Intermediate 114C 4-fluoro N (2 (2 (2(hydroxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl)benzenesulfonamide

NaBH₄ (2.93 mg, 0.077 mmol) and calcium chloride (4.30 mg, 0.039 mmol)was dissolved in THF (2 ml) and the mixture was stirred at roomtemperature for 1.5 h, followed by addition of a solution ofIntermediate 114B (45 mg, 0.039 mmol) in THF (1 mL). The mixture wasstirred at room temperature for 1.5 h. LCMS indicated a completion ofthe reaction. The mixture was diluted with water and EtOAc. The organiclayer was washed with brine, dried with sodium sulfate, andconcentrated. The crude sample was purified with a 40 g ISCO columneluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction wascollected and concentrated to give Intermediate 114C (20 mg, 0.037 mmol,96% yield) as a yellow solid. LC-MS: method C, RT=2.23 min, MS (ESI)m/z: 539 (M+H)⁺.

Example 114

To a heated suspension of Intermediate 114C (20 mg, 0.037 mmol) andsodium sulfate (1.319 mg, 9.28 μmol) in acetonitrile (2.0 mL) at 65° C.was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (5.76 μl, 0.056mmol) in acetonitrile (0.5 mL) dropwise over 40 min, The mixture wasstirred at 65° C. for 0.5 h. After the mixture was cooled to roomtemperature, it was diluted with EtOAc and quenched with NaHCO₃,extracted with EtOAc. The combined organic layer was washed with NaHCO₃and brine, dried over MgSO₄ and concentrated. The crude sample waspurified via preparative LC/MS (method D, 40-80% B over 10 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 114 (0.4mg, 0.584 μmol, 1.259% yield). LC-MS: method C, RT=2.48 min, MS (ESI)m/z: 589.20 (M+H)⁺. Analytical HPLC purity (method B): 86%.

Example 1152-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethyl6-methoxypyridin-3-ylcarbamate

Intermediate 115A: 2-(2-chlorobenzo[d]thiazol-6-yloxy)ethanol

To a solution of Intermediate I-4A (500 mg, 2.69 mmol) in DMF (10 mL)was added cesium carbonate (1755 mg, 5.39 mmol), then 2-bromoethylacetate (0.356 mL, 3.23 mmol) was added dropwise. The reaction mixturewas stirred at room temperature overnight, diluted with EtOAc and water,extracted with EtOAc. The combined organic layer was washed with brine,dried with MgSO₄ and concentrated. The crude sample was dissolved in 10ml of THF followed by addition of NaOH (5.39 mL, 1M, 5.39 mmol). Themixture was stirred at room temperature for 1 h. LCMS indicated acompletion of the reaction. The reaction mixture was diluted with EtOAcand water, extracted with EtOAc. The combined organic layer was washedwith brine, dried with MgSO₄ and concentrated. The crude sample waspurified with a 40 g ISCO column eluted with 0-100% EtOAc in hexanes for20 min. The desired fraction was collected and concentrated to giveIntermediate 115A (550 mg, 2.395 mmol, 89% yield) as off-white solid. ¹HNMR (400 MHz, chloroform-d) δ 7.73 (d, J=8.8 Hz, 1H), 7.14 (d, J=2.4 Hz,1H), 6.99 (dd, J=8.9, 2.5 Hz, 1H), 4.10-4.04 (m, 2H), 4.01-3.91 (m, 2H).LC-MS: method C, RT=1.64 min, MS (ESI) m/z: 230 (M+H)⁺.

Intermediate 115B2-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethanol

To Intermediate I-1 (512 mg, 1.524 mmol), Intermediate 115A (350 mg,1.524 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (49.8 mg, 0.061 mmol) was addedtoluene (3 mL) and EtOH (1). The mixture was sonicated for 1 min, andflushed with argon. To this was added sodium carbonate (1.524 mL, 2M,3.05 mmol). The reaction mixture was heated in a microwave reactor at130° C. for 30 min. The reaction mixture was diluted with EtOAc andwater, extracted with EtOAc (3×). The combined organic layer was washedwith brine, dried with MgSO₄ and concentrated. The residual wasdissolved in 1 ml DMSO and DCM and was loaded to a 40 g ISCO columneluted with 0-100% EtOAc in hexanes for 20 min. The desired fractionswere combined and concentrated to yield Intermediate 115B (550 mg, 1.363mmol, 89% yield) as a brown-yellow solid. ¹H NMR (400 MHz, chloroform-d)δ 8.75 (d, J=1.8 Hz, 1H), 8.67 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.77 (s,1H), 7.86-7.46 (m, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.15 (dd, J=9.0, 2.4 Hz,1H), 4.23-4.16 (m, 2H), 4.04 (d, J=4.6 Hz, 2H), 2.67 (s, 3H). ¹⁹F NMR(376 MHz, chloroform-d) δ −89.73 (s, 2F). LC-MS: method C, RT=2.31 min,MS (ESI) m/z: 404 (M+H)⁺.

Intermediate 115C2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethanol

To a solution of Intermediate 115B (550 mg, 1.363 mmol) in THF (10 mL)was added NaOMe in MeOH (4.3 M, 0.936 mL, 4.09 mmol). The mixture wasstirred at room temperature for 1 h. LCMS indicated a completion of thereaction. The reaction was quenched by 1N HCl (12 ml) and extracted withDCM (3×). The combined organic layer was washed with brine, dried withMgSO₄ and concentrated to give Intermediate 115C (400 mg, 1.089 mmol,80% yield) as a yellow solid. ¹H NMR (400 MHz, chloroform-d) δ 8.63 (d,J=1.5 Hz, 1H), 8.57 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.76 (dd, J=2.0,0.9 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.16 (dd, J=8.9, 2.5 Hz, 1H),4.27-4.18 (m, 2H), 4.14 (s, 3H), 4.08-4.01 (m, 2H), 2.66 (s, 3H). LC-MS:method C, RT=2.31 min, MS (ESI) m/z: 368 (M+H)⁺.

Intermediate 115D2-(2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yloxy)ethylcarbonochloridate

To a suspension of Intermediate 115C (150 mg, 0.408 mmol) in THF (3 mL)at room temperature was added 15% phosgene in toluene (1.440 mL, 2.041mmol). The mixture was stirred at room temperature overnight. Solventwas removed under vacuum and Intermediate 115D (175 mg, 0.407 mmol, 100%yield) was obtained as a yellow solid. It was used for the next stepwithout any purification. LC-MS: method C, RT=2.56 min, MS (ESI) m/z:430 (M+H)⁺.

Example 115

To a solution of 6-methoxypyridin-3-amine (15.16 mg, 0.122 mmol) in DCM(0.5 mL) was added Intermediate 115D (15 mg, 0.035 mmol) in THF (0.5mL), followed by DIEA (0.061 mL, 0.349 mmol). The mixture was stirred atroom temperature for 1 h. The reaction was quenched by addition of asmall amount of MeOH/water/0.1% TFA (HPLC solvent) and concentrated. Theresidual was purified via preparative LC/MS (method D, 50-100% B over 12min., then a 7-min hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to giveExample 115 (5.0 mg, 9.56 μmol, 27.4% yield). ¹H NMR (500 MHz, DMSO-d₆)δ 9.82 (br. s., 1H), 8.73 (s, 1H), 8.57 (d, J=1.4 Hz, 1H), 8.24 (br. s.,1H), 8.01 (d, J=9.1 Hz, 1H), 7.86-7.72 (m, 3H), 7.19 (dd, J=8.8, 2.5 Hz,1H), 6.79 (d, J=8.8 Hz, 1H), 4.54-4.42 (m, 2H), 4.38-4.29 (m, 2H), 4.07(s, 3H), 3.79 (s, 3H), 2.62 (s, 3H). LC-MS: method C, RT=2.23 min, MS(ESI) m/z: 518.20 (M+H)⁺. Analytical HPLC purity (method B): 99%.

Example 1162-(2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl5-cyanopyridin-3-ylcarbamate

To a solution of Intermediate 110B in THF (0.5 mL) was added asuspension of (5-cyanopyridin-3-yl)carbamic chloride (21.42 mg, 0.118mmol) (23.80 mg, 0.131 mmol) in DCM and toluene, followed by DIEA (0.046ml, 0.262 mmol). The mixture was stirred at room temperature for 30 min.LCMS indicated a completion of the reaction. The mixture was quenched by10% water/acetonitrile with 01% TFA. Solvent was removed and the crudewas purified via preparative LC/MS (method D, 50-85% B over 20 min.,then a 5-min hold at 100% B). Fractions containing the desired productwere combined and dried via centrifugal evaporation to give Example 116(9.0 mg, 0.016 mmol, 61.9% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 10.51(br. s., 1H), 8.85 (d, J=2.5 Hz, 1H), 8.72 (s, 1H), 8.65 (d, J=1.7 Hz,1H), 8.58 (d, J=1.7 Hz, 1H), 8.29 (s, 1H), 7.80 (s, 1H), 7.57 (d, J=2.2Hz, 1H), 7.03 (d, J=1.7 Hz, 1H), 4.57-4.49 (m, 2H), 4.38-4.31 (m, 2H),4.07 (s, 3H), 2.74 (s, 3H), 2.63 (s, 3H). LC-MS: method C, RT=2.52 min,MS (ESI) m/z: 527.15 (M+H)⁺. Analytical HPLC purity (method B): 95%.

Example 1172-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl(6-cyanopyridin-3-yl)carbamate

To Intermediate 110B (15 mg, 0.039 mmol) in THF (0.5 mL) was added(6-cyanopyridin-3-yl)carbamic chloride (21.42 mg, 0.118 mmol) (21.42 mg,0.118 mmol) in DCM (1 ml) followed by DIEA (0.069 ml, 0.393 mmol). Themixture was stirred at room temperature for 30 min. LCMS indicated acompletion of the reaction. The mixture was quenched by 10%water/acetonitrile with 01% TFA. Solvent was removed, the residual waspurified via preparative LC/MS (method D, 55-95% B over 10 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 117 (13.1mg, 0.025 mmol, 63.3% yield). LC-MS: method C, RT=2.55 min, MS (ESI)m/z: 527.20 (M+H)⁺. Analytical HPLC purity (method B): 98%.

Example 1182-((2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl(3-cyanophenyl)carbamate

To a solution of 3-aminobenzonitrile (14.43 mg, 0.122 mmol) in DCM (0.5mL) was added Intermediate 115D (15 mg, 0.035 mmol) in THF (1 mL)followed by DIEA (0.061 mL, 0.349 mmol). The mixture was stirred at roomtemperature overnight. The reaction was quenched by addition of a smallamount of MeOH/water/0.1% TFA (HPLC solvent) and concentrated. Theresidual was dissolved in DMSO and purified via preparative LC/MS(method D, 60-100% B over 20 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to give Example 118 (2.1 mg, 3.94 μmol, 11.29%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 10.26 (br. s., 1H), 8.74 (s, 1H),8.58 (d, J=1.4 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 7.90 (s, 1H), 7.82 (s,1H), 7.78 (d, J=2.2 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.54-7.48 (m, 1H),7.48-7.44 (m, 1H), 7.20 (dd, J=8.8, 2.5 Hz, 1H), 4.52 (d, J=4.4 Hz, 2H),4.37 (d, J=3.9 Hz, 2H), 4.08 (s, 3H), 2.63 (s, 3H). LC-MS: method C,RT=2.43 min, MS (ESI) m/z: 512.20 (M+H)⁺. Analytical HPLC purity (methodB): 96%.

Example 1192-((2-(2-methoxy-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl(2-chloropyrimidin-5-yl)carbamate

To a solution of Intermediate 110B (15.5 mg, 0.041 mmol) in THF (1 mL)was added (2-chloropyrimidin-5-yl)carbamic chloride (39.0 mg, 0.203mmol) in DCM (1 ml) followed by DIEA (0.071 ml, 0.406 mmol). The mixturewas stirred at room temperature overnight, quenched by a drop of 10%water/acetonitrile with 0.1% TFA. Solvent was removed, the residual wasdissolved in DMSO and purified via preparative LC/MS (method C, 55-100%B over 15 min., then a 5-min hold at 100% B). Fractions containing thedesired product were combined and dried via centrifugal evaporation togive Example 119 (3.7 mg, 6.61 μmol, 16.28% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 8.82 (s, 2H), 8.73 (s, 1H), 8.59 (s, 1H), 7.82 (s, 1H), 7.57(s, 1H), 7.03 (s, 1H), 4.53 (br. s., 2H), 4.35 (br. s., 2H), 4.07 (s,3H), 2.74 (s, 3H), 2.64 (s, 3H). LC-MS: method C, RT=2.54 min, MS (ESI)m/z: 537.15 (M+H)⁺. Analytical HPLC purity (method B): 96%.

Example 1205-(6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxaline

Intermediate 120A: 4-fluoro-2-hydroxy-5-methoxybenzaldehyde

To a solution of 3-fluoro-4-methoxyphenol (200 mg, 1.407 mmol) in THF (8ml) was added magnesium chloride (260 mg, 2.81 mmol), triethylamine(0.981 mL, 7.04 mmol) and paraformaldehyde (211 mg, 7.04 mmol). Thereaction mixture was heated to reflux at 80° C. under argon for 3.0 h.TLC and LCMS indicated a complete conversion of starting material. Thereaction mixture was cooled to room temperature, diluted with EtOAc,quenched with 1.0 N HCl (8.0 mL)/water and stirred at room temperaturefor 15 min until the cloudy solution turned to a clear solution. Themixture was passed through a pad of wet celite. The organic layer wascollected, washed with brine, dried over sodium sulfate andconcentrated. The crude product was purified with flash chromatography(loading in chloroform, 0% to 30% EtOAc in hexanes over 15 min using a12 g silica gel cartridge). The desired fractions were combined andconcentrated to yield Intermediate 120A (235 mg, 1.381 mmol, 98% yield)as a white solid. ¹⁹F NMR (376 MHz, Chloroform-d) δ −117.87 (s, 1F). ¹HNMR (400 MHz, chloroform-d) δ 11.09 (d, J=1.8 Hz, 1H), 9.81 (s, 1H),7.09 (d, J=9.0 Hz, 1H), 6.75 (d, J=11.9 Hz, 1H), 3.91 (s, 3H). LC-MS:method C, RT=1.45 min, MS (ESI) m/z: No (M+H)⁺.

Intermediate 120B: ethyl 6-fluoro-5-methoxybenzofuran-2-carboxylate

To a mixture of Intermediate 120A (1.7 g, 9.99 mmol) and Cs₂CO₃ (3.91 g,11.99 mmol) in acetonitrile (50 mL) was added ethyl bromoacetate (1.266mL, 10.99 mmol). The mixture was stirred at room temperature overweekend. The mixture was filtered and the filter cake was rinse withEtOAc. The combined filtrate was concentrated to a white solid of ethyl2-(5-fluoro-2-formyl-4-methoxyphenoxy)acetate. The crude sample wasadded to a solution of2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.864g, 4.00 mmol) in EtOH (10 mL). The mixture was heated at 70° C. for 2 h.TLC and LCMS indicated a completion of the reaction. The mixture wasconcentrated and the residual was purified with a 120 g ISCO columneluted with 0-100% EtOAc in hexanes for 40 min. The desired fraction wascollected and concentrated to give Intermediate 120B (1.6 g, 6.72 mmol,67.2% yield) as a white solid. ¹H NMR (400 MHz, chloroform-d) δ 7.47 (d,J=0.9 Hz, 1H), 7.35 (dd, J=10.5, 0.8 Hz, 1H), 7.16 (d, J=8.1 Hz, 1H),4.44 (q, J=7.0 Hz, 2H), 3.95 (s, 3H), 1.43 (t, J=7.2 Hz, 3H). ¹⁹F NMR(376 MHz, chloroform-d) δ −130.18 (s, 1F). LC-MS: method C, RT=1.93 min,MS (ESI) m/z: 239.1 (M+H)⁺.

Intermediate 120C: 6-fluoro-5-methoxybenzofuran

To a solution of Intermediate 120B (1.6 g, 6.72 mmol) in THF (25 mL) andMeOH (5 mL) was added NaOH (0.806 g, 20.15 mmol) in water (10 mL). Themixture was stirred at room temperature for 1 h. LCMS indicated thereaction was complete. The mixture was diluted with EtOAc and 1N HCl(pH<2), extracted with EtOAc. The combined organic layer was washed withbrine, dried over MgSO₄ and concentrated to6-fluoro-5-methoxybenzofuran-2-carboxylic acid as a white solid. LC-MS:method C, RT=1.59 min, MS (ESI) m/z: 211 (M+H)⁺. The crude acid wasredissolved in DMSO (25 mL), then silver carbonate (0.740 g, 1.35 mmol)and AcOH (0.038 mL, 0.672 mmol) was added. The mixture was heated at120° C. overnight. LCMS indicated a completion of the reaction. Themixture was filtered and the filter cake was washed with EtOAc. Thefiltrate was concentrated and purified with a 120 g ISCO column elutedwith 0-50% EtOAc in hexanes for 40 min. The desired fraction wascollected and concentrated to give Intermediate 120C (0.97 g, 5.84 mmol,87% yield) as a yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ 7.71 (d,J=2.2 Hz, 1H), 7.30 (dd, J=10.9, 0.8 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H),6.79 (dd, J=2.2, 1.1 Hz, 1H). ¹⁹F NMR (376 MHz, methanol-d₄) δ −138.84(s, 1F). LC-MS: method C, RT=1.74 min, MS (ESI) m/z: No (M+H)⁺.

Intermediate 120D: 6-fluorobenzofuran-5-ol

To a mixture of Intermediate 120C (0.73 g, 4.39 mmol) andtetrabutylammonium iodide (1.704 g, 4.61 mmol) in DCM (4 ml) at −78° C.was added boron trichloride in heptane (10.33 ml, 1.0 M, 10.33 mmol)dropwise. The mixture was stirred at −78° C. for 45 min. The coolingbath was removed and the mixture was stirred at room temperature for 3.0h. HPLC and TLC indicated a clean reaction. The mixture was poured into1.5M K₂HPO₄ with ice, stirred for 20 min, extracted with EtOAc. Theorganic layers were collected, washed with 10% Na₂S₂O₃, water, brine,dried over sodium sulfate. After evaporation of solvent, the crudeproduct was dissolved in a small amount of chloroform and charged to a40 g ISCO column eluted with hexanes for 1 min., then a 15 min gradientfrom 0% to 50% EtOAc in hexanes. The desired fractions were combined andconcentrated to give Intermediate 120D (650 mg, 4.27 mmol, 97% yield) asoff-white solid. ¹⁹F NMR (376 MHz, chloroform-d) δ −142.05 (s, 1F). ¹HNMR (400 MHz, chloroform-d) δ 7.59 (d, J=2.2 Hz, 1H), 7.29-7.26 (d, Hz1H), 7.17 (d, J=8.6 Hz, 1H), 6.73-6.64 (m, 1H), 5.00 (d, J=4.8 Hz, 1H).LC-MS: method C, RT=1.37 min, MS (ESI) m/z: No (M+H)⁺.

Intermediate 120E: tert-butyl(6-fluorobenzofuran-5-yloxy)dimethylsilane

To a stirred solution of Intermediate 120D (0.65 g, 4.27 mmol) in DMF(15 mL) was added TBDMS-Cl (0.966 g, 6.41 mmol) and imidazole (0.524 g,7.69 mmol). The reaction mixture was stirred at room temperature for 1.0h. TLC and LCMS indicated a clean reaction. The mixture was partitionedbetween EtOAc/water. The organic layer was washed with water, brine,dried over sodium sulfate. After evaporation of solvent, the crudeproduct was dissolved in a small amount of chloroform and charged to a40 g silica gel cartridge which was eluted with hexanes for 3 min., then15 min gradient from 0% to 15% EtOAc in hexanes. The desired fractionswere combined and concentrated to give Intermediate 120E (1 g, 3.75mmol, 88% yield) as clear oil. ¹H NMR (400 MHz, chloroform-d) δ 7.58 (d,J=2.2 Hz, 1H), 7.24 (dd, J=10.0, 0.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H),6.66 (dd, J=2.1, 1.0 Hz, 1H), 1.08-1.00 (m, 9H), 0.26-0.16 (m, 6H). ¹⁹FNMR (376 MHz, chloroform-d) δ −133.00 (s, 1F). LC-MS: method C, RT=2.53min, MS (ESI) m/z: 267 (M+H)⁺.

Intermediate 120F:tert-butyl(6-fluoro-7-(trimethylsilyl)benzofuran-5-yloxy) dimethylsilane

To diisopropylamine (0.594 mL, 4.17 mmol) in THF (10 mL) at −78° C. wasadded 1.6 N n-BuLi in hexanes (2.083 mL, 3.33 mmol). The mixture wasstirred at −78° C. for 0.5 h. Then Intermediate 120E (740 mg, 2.78 mmol)in THF (2 mL) was added, the mixture was stirred at −78° C. for 0.5 h.TMS-Cl in DCM (3.61 mL, 3.61 mmol) was added, and the reaction mixturewas warmed up to room temperature over 0.5 h. The reaction mixture wasdiluted with EtOAc, quenched with saturated ammonium chloride. Theorganic layer was washed with Na₂CO₃, brine, dried over sodium sulfate.After evaporation of solvent, the crude was purified with a 40 g ISCOcolumn eluted with 0-20% EtOAc in hexanes for 20 min. The desiredfraction was collected and concentrated to give Intermediate 120F (840mg, 2.481 mmol, 89% yield) as colorless oil. ¹⁹F NMR (376 MHz,chloroform-d) δ −121.09 (s, 1F). ¹H NMR (400 MHz, chloroform-d) δ 7.57(d, J=2.2 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 1.03(s, 9H), 0.46 (d, J=1.1 Hz, 9H), 0.20 (d, J=1.1 Hz, 6H). LC-MS: methodC, RT=2.24 min, MS (ESI) m/z: 339 (M+H)⁺.

Intermediate 120Gtert-butyl(6-fluoro-2-iodo-7-(trimethylsilyl)benzofuran-5-yloxy)dimethylsilane

To a solution of Intermediate 120F (840 mg, 2.481 mmol) in THF (10 mL)at −78° C. was added 1.6 N n-BuLi in hexanes (2.016 mL, 3.23 mmol). Themixture was stirred at −78° C. for 0.5 h. Then iodine (945 mg, 3.72mmol) in THF (2 mL) was added, the mixture was stirred at −78° C. for0.5 h. LCMS indicated a completion of the reaction. The reaction mixturewas diluted with EtOAc, quenched with saturated ammonium chloride. Theorganic layer was washed with Na₂S₂O₃ and brine, dried over sodiumsulfate. After evaporation of solvent, the crude was purified with a 40g ISCO column eluted with 0-20% EtOAc in hexanes for 20 min. The desiredfraction was collected and concentrated to give Intermediate 120G (880mg, 1.895 mmol, 76% yield) as colorless oil. ¹H NMR (400 MHz,chloroform-d) δ 7.00 (d, J=8.6 Hz, 1H), 6.81 (s, 1H), 1.03 (s, 9H), 0.45(d, J=1.1 Hz, 9H), 0.18 (d, J=1.1 Hz, 6H). ¹⁹F NMR (376 MHz,chloroform-d) δ −120.92 (s, 1F). LC-MS: method C, RT=2.57 min, MS (ESI)m/z: 465 (M+H)⁺.

Intermediate 120H:5-(5-(tert-butyldimethylsilyloxy)-6-fluoro-7-(trimethylsilyl)benzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxaline

To Intermediate I-1 (57.9 mg, 0.172 mmol), Intermediate 120G (80 mg,0.172 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (7.03 mg, 8.61 μmol) was addedtoluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1min, and flushed with argon. To the above mixture was added sodiumcarbonate (0.172 mL, 2M, 0.344 mmol). The reaction mixture was heated ina microwave reactor at 120° C. for 30 min. The crude reaction mixturewas directly loaded onto a 40 g ISCO column, eluted with 0-20% EtOAc inhexanes for 20 min. The desired fractions were combined and concentratedto yield Intermediate 120H (100 mg, 0.128 mmol, 74.3% yield) as a yellowoil. ¹H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 8.12 (d, J=1.8 Hz,1H), 7.97 (s, 1H), 7.63 (dd, J=1.9, 1.0 Hz, 1H), 7.86-7.47 (m, 1H), 7.17(d, J=8.6 Hz, 1H), 2.64 (s, 3H), 1.05 (s, 9H), 0.57 (d, J=1.1 Hz, 9H),0.21 (d, J=0.9 Hz, 6H). ¹⁹F NMR (376 MHz, chloroform-d) δ −89.68 (s,2F). LC-MS: method C, RT=4.63 min, MS (ESI) m/z: 547 (M+H)⁺.

Intermediate 120I6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-(trimethylsilyl)benzofuran-5-ol

To solution of Intermediate 120H (100 mg, 0.128 mmol) in THF (3 mL) atroom temperature was added sodium methoxide in MeOH (0.095 mL, 4.37M,0.448 mmol). The reaction mixture was stirred at room temperature for 30min. TLC and LCMS indicated a completion of the reaction. The reactionmixture was quenched with saturated NH₄Cl, diluted with EtOAc. Theorganic layer was washed with saturated sodium bicarbonate, brine, driedover MgSO₄ and concentrated. The crude was purified with a 12 g ISCOcolumn eluted with 0-50% EtOAc in hexanes for 15 min. The desiredfraction was collected and concentrated to give Intermediate 120I (69mg, 0.122 mmol, 95% yield) as a yellow solid. ¹H NMR (400 MHz,chloroform-d) δ 8.51 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.97 (s, 1H), 7.62(dd, J=1.8, 0.9 Hz, 1H), 7.23 (d, J=9.2 Hz, 1H), 4.12 (s, 3H), 0.58 (s,9H). LC-MS: method C, RT=2.77 min, MS (ESI) m/z: 397 (M+H)⁺.

Intermediate 120J:6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-ol

To a solution of Intermediate 120I (69 mg, 0.122 mmol) in THF (2 mL) wasadded AcOH (0.021 mL, 0.365 mmol) followed by TBAF (0.488 mL, 0.488mmol). The mixture was stirred at room temperature for 3 h. LCMSindicated a completion of the reaction. Solvent was removed and theresidual was purified with a 12 g ISCO column eluted with 0-70%EtOAc/hexanes for 20 min. The desired fraction was collected andconcentrated to give Intermediate 120J (30 mg, 0.093 mmol, 76% yield).¹H NMR (400 MHz, chloroform-d) δ 8.48 (s, 1H), 8.42-8.38 (m, 1H), 7.95(s, 1H), 7.84 (s, 1H), 7.50 (s, 1H), 7.16 (d, J=10.6 Hz, 1H), 7.12-7.06(m, 1H), 4.07-3.98 (m, 3H), 2.51 (s, 3H). ¹⁹F NMR (376 MHz,chloroform-d) δ −137.18 (s, 1F). LC-MS: method C, RT=2.42 min, MS (ESI)m/z: 325 (M+H)⁺.

Example 120

To a solution of Intermediate 120J (15 mg, 0.046 mmol) in DMF (1 mL) wasadded Cs₂CO₃ (45.2 mg, 0.139 mmol) and Met (0.014 mL, 0.231 mmol). Themixture was stirred at room temperature for 2 h. LCMS indicated acompletion of the reaction. The mixture was filtered. The filtrate waspurified via preparative LC/MS (method D, 65-100% B over 20 min., then a5-min hold at 100% B). Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 120 (2.6mg, 7.45 μmol, 16.12% yield). ¹H NMR (500 MHz, chloroform-d) δ 8.51 (s,1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 7.33 (d, J=10.5 Hz, 1H),7.19 (d, J=8.3 Hz, 1H), 4.12 (s, 3H), 3.96 (s, 3H), 2.62 (s, 3H). LC-MS:method C, RT=2.59 min, MS (ESI) m/z: 338.9 (M+H)⁺. Analytical HPLCpurity (method B): 97%.

Example 1215-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline

Intermediate 121A: 7-chloro-6-fluoro-5-methoxybenzofuran

To diisopropylamine (0.270 mL, 1.896 mmol) in THF (5 mL) at −78° C. wasadded 1.6 N n-BuLi in hexanes (0.948 mL, 1.517 mmol). The mixture wasstirred at −78° C. for 0.5 h. Intermediate 120C (210 mg, 1.264 mmol) inTHF (1 mL) was added, the mixture was stirred at −78° C. for 0.5 h.Hexachloroethane (449 mg, 1.896 mmol) in THF (1 mL) was added, and thereaction mixture was stirred at −78° C. for 0.5 h. The reaction mixturewas diluted with EtOAc, quenched with saturated ammonium chloride. Theorganic layer was washed with Na₂SO₃, brine, dried over sodium sulfateand concentrated. The crude sample was purified with a 40 g ISCO columneluted with 0-70% EtOAc in hexanes for 20 min. The desired fraction wascollected and concentrated to give Intermediate 121A (240 mg, 1.196mmol, 95% yield) as a white solid. ¹H NMR (400 MHz, chloroform-d) δ 7.67(d, J=2.0 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 3.94(s, 3H). ¹⁹F NMR (376 MHz, chloroform-d) δ −140.56 (s, 1F). LC-MS:method C, RT=2.01 min, MS (ESI) m/z: No (M+H)⁺.

Intermediate 121B: 7-chloro-6-fluoro-2-iodo-5-methoxybenzofuran

To a solution of Intermediate 121A (240 mg, 1.196 mmol) in THF (5 mL) at−78° C. was added 1.6 N n-BuLi in hexanes (0.972 mL, 1.555 mmol). Themixture was stirred at −78° C. for 0.5 h. Iodine (456 mg, 1.795 mmol) inTHF (2 mL) was added, and the mixture was stirred at −78° C. for 0.5 h.The mixture was warmed up to room temperature and continued stirring for1 h. The reaction mixture was diluted with EtOAc, quenched withsaturated ammonium chloride. The organic layer was washed with Na₂S₂O₃,brine, dried over sodium sulfate. The crude sample was purified with a12 g ISCO column eluted with 0-20% EtOAc in hexanes for 20 min. Thedesired fraction was collected and concentrated to give Intermediate121B (280 mg, 0.686 mmol, 57.3% yield) as colorless oil. ¹⁹F NMR (376MHz, chloroform-d) δ −140.34 (s, 1F). ¹H NMR (400 MHz, chloroform-d) δ6.96 (d, J=7.3 Hz, 1H), 6.92 (s, 1H), 3.93 (s, 3H). LC-MS: method C,RT=2.24 min, MS (ESI) m/z: No (M+H)⁺.

Example 121

To Intermediate I-2 (11.37 mg, 0.049 mmol), Intermediate 121B (20 mg,0.049 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.001 mg, 2.450 μmol) was addedtoluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1min, and flushed with argon. To this mixture was added Na₂CO₃ (0.049 mL,2M, 0.098 mmol). The reaction mixture was heated in a microwave reactorat 120° C. for 30 min. The crude reaction mixture was directly loadedonto a 12 g ISCO column, eluted with 0-50% EtOAc in hexanes for 20 min.The desired fractions were combined and concentrated. The sample wasredissolved in DMSO and further purified via preparative LC/MS (methodD, 65-100% B over 15 min., then a 5-min hold at 100% B). Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give Example 121 (4.7 mg, 0.012 mmol, 24.55% yield). ¹HNMR (500 MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.90(s, 1H), 7.56 (d, J=7.7 Hz, 1H), 4.79 (s, 2H), 3.93 (s, 3H), 3.46 (s,3H), 2.66 (s, 3H). LC-MS: method C, RT=2.55 min, MS (ESI) m/z: 387.1(M+H)⁺. Analytical HPLC purity (method B): 99%.

Example 1225-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxy-7-methylquinoxaline

To Intermediate I-1 (16.47 mg, 0.049 mmol), Intermediate 121B (20 mg,0.049 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.001 mg, 2.450 μmol) was addedtoluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1min, and flushed with argon. To this was added sodium carbonate (0.049mL, 2M, 0.098 mmol). The reaction mixture was heated in a microwavereactor at 120° C. for 30 min. The crude reaction mixture was directlyloaded onto a 12 g ISCO column, eluted with 0-20% EtOAc in hexane for 20min. The desired fractions were combined and concentrated to yield5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-(difluoromethoxy)-7-methylquinoxalineas a yellow oil. LC-MS: method C, RT=2.81 min, MS (ESI) m/z: 409 (M+H)⁺.The above sample was dissolved in THF (1 ml) and sodium methoxide (0.036mL, 4.37M, 0.172 mmol) was added. The mixture was stirred at roomtemperature for 30 min, quenched with a drop of 10% water/MeOH with 0.1%TFA (HPLC solvent) and concentrated. The crude was redissolved in DMSOand purified via preparative LC/MS (method C, 60-100% B over 20 min.,then a 5-min hold at 100% B). Fractions containing the desired productwere combined and dried via centrifugal evaporation to give Example 122(0.8 mg, 2.146 μmol, 4.38% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (s,1H), 8.13 (s, 1H), 8.07 (s, 1H), 7.74 (s, 1H), 7.57 (d, J=7.7 Hz, 1H),4.09 (s, 3H), 3.95 (s, 3H), 2.63 (s, 3H). LC-MS: method C, RT=2.76 min,MS (ESI) m/z: 373.05 (M+H)⁺. Analytical HPLC purity (method B): 100%.

Example 1232-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl(2-methylpyridin-4-yl)carbamate

Intermediate 123A: 6-fluoro-2-iodobenzofuran-5-ol

To a solution of Intermediate 120G (64 mg, 0.138 mmol) in THF (1 mL) wasadded TBAF (0.413 mL, 0.413 mmol). The mixture was stirred at roomtemperature for 1 h. Solvent was removed under vacuum and the residualwas purified with a 12 g ISCO column eluted with 0-70% EtOAc in hexanesfor 15 min. The desired fraction was collected and concentrated to giveIntermediate 123A (38 mg, 0.137 mmol, 99% yield) as white solid. ¹⁹F NMR(376 MHz, chloroform-d) δ −141.74 (s, 1F). ¹H NMR (400 MHz,chloroform-d) δ 7.27-7.23 (m, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.86 (d,J=0.9 Hz, 1H), 5.10-4.99 (m, 1H). LC-MS: method C, RT=1.84 min, MS (ESI)m/z: No (M+H)⁺.

Intermediate 123B:6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-ol

To Intermediate I-1 (45.9 mg, 0.137 mmol), Intermediate 123A (38 mg,0.137 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (5.58 mg, 6.83 μmol) was addedtoluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1min, and flushed with argon. To this was added sodium carbonate (0.137mL, 2M, 0.273 mmol). The reaction mixture was heated in a microwavereactor at 120° C. for 30 min. The crude reaction mixture was directlyloaded onto a 12 g ISCO column, eluted with 0-50% EtOAc in hexanes for15 min. The desired fractions were combined and concentrated to yieldIntermediate 123B (78 mg, 0.130 mmol, 95% yield) as a yellow solid. ¹HNMR (400 MHz, chloroform-d) δ 8.65 (s, 1H), 8.20 (s, 1H), 8.01 (s, 1H),7.66 (s, 1H), 7.33 (d, J=10.1 Hz, 1H), 2.65 (s, 3H). ¹⁹F NMR (376 MHz,chloroform-d) δ −89.71 (s, 2F), −140.50 (s, 1F). LC-MS: method C,RT=2.37 min, MS (ESI) m/z: 361 (M+H)⁺.

Intermediate 123C2-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethanol

To a solution of Intermediate 123B (49.4 mg, 0.137 mmol) in DMF (2 mL)was added Cs₂CO₃ (134 mg, 0.411 mmol) and 2-bromoethyl acetate (0.031mL, 0.274 mmol). The mixture was stirred at room temperature for 1 h.LCMS indicated a completion of the reaction. The mixture was dilutedwith EtOAc and water, extracted with EtOAc. The combined organic layerwas washed with brine, dried with MgSO₄ and concentrated. LC-MS: methodC, RT=2.53 min, MS (ESI) m/z: 447 (M+H)⁺. The crude sample wasredissolved in THF (1 ml) and sodium methoxide (0.094 mL, 4.37M, 0.411mmol) was added. The mixture was stirred at room temperature for 30 min,diluted with EtOAc and saturated NH₄Cl, extracted with EtOAc. Thecombined organic layer was washed with saturated NaHCO₃, brine, driedover MgSO₄ and concentrated. The crude sample was dissolved in DMF andload on a 40 g ISCO column, eluted with 0-100% EtOAc in hexanes for 20min. The desired fraction was collected and concentrated to giveIntermediate 123C (50 mg, 0.136 mmol, 99% yield) as a yellow solid. ¹⁹FNMR (376 MHz, methanol-d₄) δ −136.00 (s, 1F). ¹H NMR (400 MHz,methanol-d₄) δ 8.51 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 8.02 (d, J=0.9 Hz,1H), 7.62 (dd, J=1.8, 0.9 Hz, 1H), 7.38 (dd, J=10.8, 0.9 Hz, 1H), 7.34(d, J=8.4 Hz, 1H), 4.19-4.16 (m, 2H), 4.11 (s, 3H), 3.97-3.92 (m, 2H),2.61 (s, 3H). LC-MS: method C, RT=2.39 min, MS (ESI) m/z: 369 (M+H)⁺.

Intermediate 123D2-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzofuran-5-yloxy)ethylcarbonochloridate

To a solution of Intermediate 123C (45 mg, 0.122 mmol) in THF (2 mL) wasadded 15% phosgene in toluene (0.431 mL, 0.611 mmol), and the mixturewas stirred at room temperature overnight. Solvent was removed undervacuum to give Intermediate 123D as a yellow solid. It was used for thenext step without any purification. LC-MS: method C, RT=2.63 min, MS(ESI) m/z: 431 (M+H)⁺.

Example 123

To a solution of Intermediate 123D (10 mg, 0.023 mmol) in THF (1 mL) wasadded 2-methylpyridin-4-amine (7.53 mg, 0.070 mmol) in DCM (0.5 mL)followed by DIEA (0.041 mL, 0.232 mmol). The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of the reaction. Thereaction was quenched by addition of a small amount of 10%MeOH/water/0.1% TFA (HPLC solvent). Solvent was removed under vacuum.The residual was dissolved in DMSO and purified via preparative LC/MS(method C, 40-80% B over 20 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to give Example 123 (2.7 mg, 5.37 μmol, 23.15%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.20 (br. s., 1H), 8.67 (s, 1H),8.50 (d, J=6.6 Hz, 1H), 8.03 (s, 2H), 7.76-7.65 (m, 4H), 7.57 (d, J=8.5Hz, 1H), 4.60 (br. s., 2H), 4.41 (br. s., 2H), 4.06 (s, 3H), 2.58 (br.s., 6H). LC-MS: method C, RT=1.99 min, MS (ESI) m/z: 503.15 (M+H)⁺.Analytical HPLC purity (method B): 100%.

Example 124(8-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)methanol

To Intermediate I-27 (14.22 mg, 0.035 mmol), Intermediate 121B (14.22mg, 0.035 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (1.423 mg, 1.742 μmol) was added toluene(0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1 min, andflushed with argon. To this mixture was added sodium carbonate (0.035mL, 2M, 0.070 mmol). The reaction mixture was heated in a microwavereactor at 120° C. for 30 min. The crude reaction mixture was directlyloaded onto a 12 g ISCO column and eluted with 0-20% EtOAc in hexanesfor 20 min. The desired fractions were combined and concentrated toyield7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(7-chloro-6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxyquinoxalineas an off-white solid. The sample was dissolved in 2 ml of DCM and TFA(0.013 mL, 0.174 mmol) was added. The mixture was stirred at roomtemperature for 1 h. TLC indicated a small conversion. TBAF (0.070 mL,0.070 mmol) was added to the mixture and stirred at room temperatureovernight. LCMS indicate a completion of the reaction. Solvent wascompletely removed and the residual was purified via preparative LC/MS(method C, 45-90% B over 20 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to give Example 124 (3.0 mg, 7.33 μmol, 21.04%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.17 (s, 1H), 8.09 (s,1H), 7.79 (s, 1H), 7.52 (d, J=7.4 Hz, 1H), 5.60 (t, J=5.2 Hz, 1H), 4.80(d, J=5.5 Hz, 2H), 4.07 (s, 3H), 3.93 (s, 3H). LC-MS: method C, RT=2.20min, MS (ESI) m/z: 388.90 (M+H)⁺. Analytical HPLC purity (method B):95%.

Example 125(8-(6-fluoro-5-methoxybenzofuran-2-yl)-3-methoxyquinoxalin-6-yl)methanol

Intermediate 125A2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-6-fluorobenzofuran-5-ol

To Intermediate I-27 (90 mg, 0.209 mmol), Intermediate 123A (58.1 mg,0.209 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (8.54 mg, 10.45 μmol) was addedtoluene (0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1min, and flushed with argon. To this was added sodium carbonate (0.209mL, 2M, 0.418 mmol). The reaction mixture was heated in a microwavereactor at 120° C. for 30 min. The crude reaction mixture was directlyloaded onto a 40 g ISCO column which was eluted with 0-50% EtOAc inhexanes for 20 min. The desired fractions were combined and concentratedto yield Intermediate 125A (105 mg, 0.185 mmol, 88% yield) as a yellowoil. ¹H NMR (400 MHz, chloroform-d) δ 8.55 (s, 1H), 8.18 (d, J=2.0 Hz,1H), 8.00 (d, J=0.9 Hz, 1H), 7.82-7.77 (m, 1H), 7.31 (dd, J=10.0, 0.8Hz, 1H), 7.25-7.22 (m, 1H), 5.00 (s, 2H), 4.14 (s, 3H), 1.02 (d, J=5.7Hz, 9H), 0.19 (s, 6H). LC-MS: method C, RT=2.97 min, MS (ESI) m/z: 455(M+H)⁺.

Example 125

To a solution of Intermediate 125A (14 mg, 0.031 mmol) in DMF (1 mL) wasadded Cs₂CO₃ (30.1 mg, 0.092 mmol) and MeI (9.63 μl, 0.154 mmol). Themixture was stirred at room temperature for 2 h. LCMS indicated acompletion of the reaction. The mixture was loaded to 12 g ISCO columnwhich was eluted with 0-50% EtOAc in hexanes for 15 min. The desiredfraction was combined and concentrated to give7-(((tert-butyldimethylsilyl)oxy)methyl)-5-(6-fluoro-5-methoxybenzofuran-2-yl)-2-methoxyquinoxalineas a light yellow solid. The intermediate was dissolved in THF (2 ml),and TBAF (0.062 mL, 0.062 mmol) was added. The mixture was stirred atroom temperature for 1 h. LCMS indicated a completion of the reaction.Solvent was removed, the residual was purified via preparative LC/MS(method D, 35-75% B over 15 min., then a 5-min hold at 100% B).Fractions containing the desired product were combined and dried viacentrifugal evaporation to give Example 125 (3.3 mg, 9.13 μmol, 29.6%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.18 (d, J=1.7 Hz,1H), 8.06 (d, J=0.8 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.70 (d, J=11.0 Hz,1H), 7.51 (d, J=8.8 Hz, 1H), 5.57 (t, J=5.8 Hz, 1H), 4.78 (d, J=5.5 Hz,2H), 4.08 (s, 3H), 3.90 (s, 3H). LC-MS: method C, RT=1.95 min, MS (ESI)m/z: 355.15 (M+H)⁺. Analytical HPLC purity (method B): 98%.

Example 1262-((6-fluoro-2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)benzofuran-5-yl)oxy)ethyl(2-methylpyridin-4-yl)carbamate

Intermediate 126A2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-6-fluorobenzofuran-5-yloxy)ethanol

To a solution of Intermediate 125A (90 mg, 0.158 mmol) in DMF (2 mL) wasadded Cs₂CO₃ (155 mg, 0.475 mmol) and 2-bromoethyl acetate (0.035 mL,0.317 mmol). The mixture was stirred at room temperature overnight. LCMSindicated a completion of the reaction. The mixture was diluted withEtOAc and water, extracted with EtOAc. The combined organic layer waswashed with brine, dried over MgSO₄ and concentrated. The crude samplewas dissolved in THF (2 ml) and NaOMe (0.109 mL, 4.37M, 0.475 mmol) wasadded. The mixture was stirred at room temperature for 30 min. LCMSindicated a completion of the reaction. The mixture was diluted withEtOAc and saturate NH₄Cl, extracted with EtOAc. The combined organiclayer was washed with NaHCO₃, brine, dried over MgSO₄ and concentrated.The crude sample was dissolved in a small amount of DMF, loaded on a 40g ISCO column, eluted with 0-100% EtOAc in hexanes for 20 min. Thedesired fraction was collected and concentrated to give Intermediate126A (47 mg, 0.075 mmol, 47.6% yield). ¹H NMR (400 MHz, chloroform-d) δ8.53 (s, 1H), 8.18 (d, J=1.8 Hz, 1H), 8.01 (d, J=0.7 Hz, 1H), 7.83-7.76(m, 1H), 7.32 (dd, J=10.5, 0.8 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 5.00 (s,2H), 4.23-4.16 (m, 2H), 4.14 (s, 3H), 4.01 (dt, J=8.9, 4.3 Hz, 2H),1.05-1.01 (m, 9H), 0.19 (s, 6H). LC-MS: method C, RT=2.98 min, MS (ESI)m/z: 499 (M+H)⁺.

Intermediate 126B2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-6-fluorobenzofuran-5-yloxy)ethylcarbonochloridate

To the solution of Intermediate 126A (47 mg, 0.075 mmol) and DIEA (0.066ml, 0.377 mmol) in THF (1 mL) was added to 15% phosgene in toluene(0.160 ml, 0.226 mmol). The mixture was stirred at room temperature for3 h. Solvent was removed under vacuum to give Intermediate 126B as ayellow solid. It was used for the next step without any purification.LC-MS: method C, RT=3.46 min, MS (ESI) m/z: 561 (M+H)⁺.

Example 126

To a solution of Intermediate 126B (10 mg, 0.018 mmol) in THF (1 mL) wasadded 2-methylpyridin-4-amine (5.78 mg, 0.053 mmol) in DCM (0.5 mL)followed by DIEA (0.031 mL, 0.178 mmol). The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of the reaction. TBAF(0.071 mL, 0.071 mmol) was added, and the mixture was stirred at roomtemperature overnight. The reaction mixture was quenched by addition ofa small amount of MeOH/water/0.1% TFA (HPLC solvent). Solvent wasremoved under vacuum. The residual was dissolved in DMSO and purifiedvia preparative LC/MS (method D, 30-70% B over 20 min., then a 5-minhold at 100% B). Fractions containing the desired product were combinedand dried via centrifugal evaporation to give Example 126 (2.3 mg, 4.26μmol, 23.89% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.70 (s,1H), 8.28 (d, J=5.8 Hz, 1H), 8.18 (d, J=1.7 Hz, 1H), 8.05 (s, 1H), 7.78(s, 1H), 7.73 (d, J=10.7 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.37 (s, 1H),7.33 (d, J=5.5 Hz, 1H), 5.57 (s, 1H), 4.78 (d, J=5.0 Hz, 2H), 4.57-4.45(m, 2H), 4.42-4.32 (m, 2H), 4.07 (s, 3H), 2.41 (s, 3H). LC-MS: method C,RT=1.48 min, MS (ESI) m/z: 519.20 (M+H)⁺. Analytical HPLC purity (methodB): 96%.

Example 1273-methoxy-8-(6-methoxybenzo[d]thiazol-2-yl)quinoxalin-6-yl)methanol

To Intermediate I-27 (10.6 mg, 0.025 mmol),2-bromo-6-methoxybenzo[d]thiazole (6.01 mg, 0.025 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (1.006 mg, 1.231 μmol) was added toluene(0.75 mL) and EtOH (0.25 mL). The mixture was sonicated for 1 min, andflushed with argon. To this was added sodium carbonate (0.025 mL, 2M,0.049 mmol). The reaction mixture was heated in a microwave reactor at120° C. for 30 min. The crude reaction mixture was directly loaded on a12 g ISCO column, eluted with 0-50% EtOAc in hexanes for 15 min. Thedesired fraction was collected and concentrated to yield2-(7-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxyquinoxalin-5-yl)-6-methoxybenzo[d]thiazole.LC-MS: method C, RT=3.4 min, MS (ESI) m/z: 468 (M+H)⁺. The sample wasredissolved in THF (1 ml) and TBAF (0.074 mL, 0.074 mmol) was added. Themixture was stirred at room temperature for 30 min. LCMS indicated acompletion of the reaction. The mixture was concentrated and purifiedvia preparative LC/MS (method C, 30-70% B over 20 min., then a 5-minhold at 100% B). Fractions containing the desired product were combinedand dried via centrifugal evaporation to give Example 127 (1.4 mg, 3.80μmol, 15.44% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.72 (s,1H), 8.01 (d, J=8.9 Hz, 1H), 7.91 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.16(dd, J=9.0, 2.3 Hz, 1H), 4.82 (d, J=5.5 Hz, 2H), 4.09 (s, 3H). LC-MS:method C, RT=1.82 min, MS (ESI) m/z: 345.10 (M+H)⁺. Analytical HPLCpurity (method B): 100%.

Example 1282-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl6-methylpyridin-3-ylcarbamate

Intermediate 128A: 2-(2-chloro-4-methylbenzo[d]thiazol-6-yloxy)ethanol

To a suspension of Intermediate 89B (500 mg, 2.504 mmol) in DMF (10 mL)was added cesium carbonate (1.63 g, 5.01 mmol). Then 2-bromoethylacetate (0.331 mL, 3.01 mmol) was added dropwise. The reaction mixturewas stirred at room temperature overnight. LCMS indicated a completionof the reaction. NaOH (2.504 mL, 2M, 5.01 mmol) was added to thereaction mixture, followed by MeOH (1 ml). The mixture was stirred atroom temperature for 1 h. LCMS indicated a completion of the reaction.The reaction mixture was diluted with EtOAc and water, extracted withEtOAc, the combined organic layer was washed with brine, dried withMgSO₄ and concentrated. The crude sample was purified with a 40 g ISCOcolumn eluted with 0-100% EtOAc in hexane for 20 min. The desiredfraction was collected and concentrated to give Intermediate 128A (600mg, 2.462 mmol, 98% yield). ¹H NMR (400 MHz, chloroform-d) δ 7.09 (d,J=2.2 Hz, 1H), 6.97-6.85 (m, 1H), 4.24-4.09 (m, 2H), 4.00 (d, J=3.7 Hz,2H), 2.66 (s, 3H). LC-MS: method C, RT=1.82 min, MS (ESI) m/z: 244(M+H)⁺.

Intermediate 128B2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethanol

To Intermediate 124E (50 mg, 0.116 mmol), Intermediate 128A (28.3 mg,0.116 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (4.74 mg, 5.81 μmol) was addedtoluene (1.5 mL) and EtOH (0.5 mL). The mixture was sonicated for 1 min,and flushed with argon. To this was added sodium carbonate (0.116 mL,2M, 0.232 mmol). The reaction mixture was heated in a microwave reactorat 130° C. for 30 min. The crude reaction mixture was directly loaded to12 g ISCO column eluted with 0% to 100% EtOAc in hexanes over 15 min.The desired fractions were combined and concentrated to yieldIntermediate 128B (80 mg, 0.109 mmol, 94% yield) as a yellow solid. ¹HNMR (400 MHz, chloroform-d) δ 8.80 (d, J=2.0 Hz, 1H), 8.58 (s, 1H),7.94-7.90 (m, 1H), 7.27 (s, 1H), 6.96 (dd, J=2.4, 0.9 Hz, 1H), 5.05 (s,2H), 4.20-4.16 (m, 2H), 4.15 (s, 3H), 4.05-3.98 (m, 2H), 2.82 (s, 3H),1.04 (s, 9H), 0.21-0.20 (m, 6H). LC-MS: method C, RT=3.07 min, MS (ESI)m/z: 512 (M+H)⁺.

Intermediate 128C2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethylcarbonochloridate

To a solution of Intermediate 128B (110 mg, 0.193 mmol) and DIEA (0.169ml, 0.967 mmol) in THF (2 ml) was added 15% phosgene in toluene (0.409ml, 0.580 mmol). The reaction mixture was stirred at room temperatureovernight and then concentrated to give Intermediate 128C which was usedfor next step without purification. LC-MS: method C, RT=3.64 min, MS(ESI) m/z: 574 (M+H)⁺.

Intermediate 128D2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl6-methylpyridin-3-ylcarbamate

To a solution of Intermediate 128C (16.5 mg, 0.029 mmol) in DCM (1 mL)was added 6-methylpyridin-3-amine (9.32 mg, 0.086 mmol) in DCM (0.5 mL)and DIEA (0.050 mL, 0.287 mmol). The mixture was stirred at roomtemperature for 1 h. The reaction mixture was loaded to a 12 g ISCOcolumn, eluted with 0-100% EtOAc in hexane for 15 min. The desiredfraction was collected and concentrated to give Intermediate 128D (18mg, 0.028 mmol, 97% yield). ¹H NMR (400 MHz, chloroform-d) δ 8.81 (d,J=2.0 Hz, 1H), 8.58 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.92-7.90 (m, 1H),7.85 (br. s., 1H), 7.26 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.97 (dd,J=2.4, 0.9 Hz, 1H), 6.82-6.69 (m, 1H), 5.05 (s, 2H), 4.62-4.54 (m, 2H),4.34-4.28 (m, 2H), 4.15 (s, 3H), 2.82 (s, 3H), 2.52 (s, 3H), 1.07-1.01(m, 9H), 0.22-0.18 (m, 6H). LC-MS: method C, RT=2.48 min, MS (ESI) m/z:646 (M+H)⁺.

Example 128

To a solution of Intermediate 128D (18 mg, 0.028 mmol) in DCM (1 mL) wasadded TBAF (0.139 mL, 0.139 mmol), the mixture was stirred at roomtemperature for 1 h. Solvent was removed, the residual was dissolved inDMSO and purified via preparative LC/MS (method D, 30-70% B over 20min., then a 5-min hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to giveExample 128 (3.0 mg, 5.53 μmol, 19.84% yield). ¹H NMR (500 MHz, DMSO-d₆)δ 10.05 (br. s., 1H), 8.73 (s, 1H), 8.71 (br. s., 1H), 8.55 (br. s.,1H), 7.92 (d, J=15.3 Hz, 1H), 7.86 (br. s., 1H), 7.55 (br. s., 1H), 7.32(br. s., 1H), 7.02 (br. s., 1H), 4.81 (br. s., 2H), 4.48 (br. s., 2H),4.33 (br. s., 2H), 4.08 (s, 3H), 2.88 (s, 3H), 2.43 (br. s., 3H). LC-MS:method C, RT=1.49 min, MS (ESI) m/z: 532.20 (M+H)⁺. Analytical HPLCpurity (method B): 98%.

Example 1292-(2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl2-methylpyridin-4-ylcarbamate

Intermediate 129A2-(2-(7-((tert-butyldimethylsilyloxy)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yloxy)ethyl2-methylpyridin-4-ylcarbamate

To a solution of Intermediate 128C (16.5 mg, 0.029 mmol) in DCM (1 mL)was added 2-methylpyridin-4-amine (9.32 mg, 0.086 mmol) in DCM (0.5 mL)and DIEA (0.050 mL, 0.287 mmol). The mixture was stirred at roomtemperature for 1 h. LCMS indicated a completion of reaction. Thereaction mixture was loaded to a 12 g ISCO column, eluted with 0-100%EtOAc in hexanes for 15 min. The desired fraction was collected andconcentrated to give Intermediate 129A (17 mg, 0.026 mmol, 92% yield).¹H NMR (400 MHz, chloroform-d) δ 8.81 (d, J=2.0 Hz, 1H), 8.59 (s, 1H),8.37 (d, J=4.2 Hz, 1H), 7.94-7.90 (m, 1H), 7.29-7.22 (m, 1H), 7.14 (d,J=4.2 Hz, 1H), 6.97 (dd, J=2.4, 0.9 Hz, 1H), 6.87 (br. s., 1H), 5.05 (s,2H), 4.64-4.56 (m, 2H), 4.35-4.29 (m, 2H), 4.15 (s, 3H), 2.82 (s, 3H),2.53 (s, 3H), 1.06-1.01 (m, 10H), 0.23-0.18 (m, 6H). LC-MS: method C,RT=2.46 min, MS (ESI) m/z: 646 (M+H)⁺.

Example 129

To a solution of Intermediate 129A (17 mg, 0.026 mmol) in DCM (1 mL) wasadded TBAF (0.132 mL, 0.132 mmol), the mixture was stirred at roomtemperature for 1 h. Solvent was removed and the residual was dissolvedin DMSO and purified via preparative LC/MS (method D, 30-70% B over 25min., then a 5-min hold at 100% B). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to giveExample 129 (2.9 mg, 5.40 μmol, 20.52% yield). ¹H NMR (500 MHz, DMSO-d₆)δ 8.70 (d, J=9.2 Hz, 2H), 8.25 (br. s., 1H), 7.88 (s, 1H), 7.53 (s, 1H),7.31 (d, J=16.2 Hz, 2H), 7.01 (s, 1H), 4.81 (d, J=4.3 Hz, 2H), 4.50 (br.s., 2H), LC-MS: method C, RT=1.55 min, MS (ESI) m/z: 532.20 (M+H)⁺.Analytical HPLC purity (method B): 99%.

Example 130 5-(benzofuran-2-yl)-2-methoxy-7-methyl-1,6-naphthyridine

Intermediate 130A:(E)-2-(2-(dimethylamino)prop-1-en-1-yl)-6-methoxynicotinonitrile

6-methoxy-2-methylnicotinonitrile (200 mg, 1.350 mmol) was dissolved inDMF (1350 μL) and N,N-dimethylacetamide dimethyl acetal (987 μL, 6.75mmol) and heated to 150° C. for 24 hours. The reaction mixture wascooled to ambient temperature and concentrated in vacuo. The crudematerial was purified by column chromatography (ISCO, 12 g silica gelcolumn, 17 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 130A (177.9 mg, 0.819 mmol, 60.7%) as a yellow solid:LC-MS: Ketone product mass observed, Method H, RT=0.72 min, MS (ESI)m/z: 191.2 (M+H)⁺.

Intermediate 130B: 2-methoxy-7-methyl-1,6-naphthyridin-5-ol

Intermediate 130A (178 mg, 0.819 mmol) was dissolved in CHCl₃ (6145 μL),AcOH (1024 μL), and HBr (1024 μL) and stirred for 18 hours. The reactionmixture was diluted with 1 N NaOH and extracted thrice with EtOAc. Thecombined organic layers were washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 24 g silica gel column, 19 minute gradientfrom 0 to 100% EtOAc in hexanes) to give Intermediate 130B (51.6 mg,0.271, 33.1%) as a white solid: ¹H NMR (400 MHz, METHANOL-d₄) δ 8.34 (d,J=8.8 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.44 (br. s., 1H), 4.02 (d, J=2.8Hz, 3H), 2.33 (s, 3H); LC-MS: Method H, RT=0.7 min, MS (ESI) m/z: 191.2(M+H)⁺.

Intermediate 130C: 2-methoxy-7-methyl-1,6-naphthyridin-5-yltrifluoromethanesulfonate

Intermediate 130B (0.0516 g, 0.271 mmol), pyridine (0.055 mL, 0.678mmol), and DIEA (0.104 mL, 0.597 mmol) were dissolved in DCM (13.56 mL).Triflic anhydride (0.092 mL, 0.543 mmol) was added and the reactionmixture stirred for 1.5 hours. The reaction mixture was concentrated invacuo. 2D TLC was used to determine if the triflate product was unstableto silica gel and there was a slight bit of decomposition observed.Therefore, the reaction mixture was filtered through a pad of silica gelin a fritted funnel with rapid DCM elution and concentrated in vacuo togive Intermediate 130C (77.5 mg, 0.240 mmol, 89%) as a red oil: ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.14 (d, J=9.0 Hz, 1H), 7.52 (s, 1H), 7.00 (d,J=9.0 Hz, 1H), 4.09 (s, 3H), 2.63 (s, 3H); LC-MS: Method H, RT=1.10 min,MS (ESI) m/z: 323.0 (M+H)⁺.

Example 130

Intermediate 130C (30 mg, 0.093 mmol) and benzofuran-2-ylboronic acid(22.61 mg, 0.140 mmol) were dissolved in toluene (698 μL) and EtOH (233μL). PdCl₂(dppf)-CH₂Cl₂ (4.56 mg, 5.59 μmol) was added and the reactionmixture was degassed by bubbling with argon for 15 minutes. Sodiumcarbonate (2 M, 55.9 μL, 0.112 mmol) was added and the reaction mixturewas degassed for 5 minutes, then sealed and heated to 90° C. in themicrowave for 30 minutes. The reaction mixture was purified bypreparative HPLC (Method D, 30 to 80% B in 10 minutes) to give Example130 (9.8 mg, 0.033 mmol, 35.2%): ¹H NMR (500 MHz, METHANOL-d₄) δ 8.95(d, J=9.4 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.57(s, 1H), 7.51 (s, 1H), 7.40 (t, J=7.3 Hz, 1H), 7.35-7.29 (m, 1H), 7.02(d, J=9.4 Hz, 1H), 4.11 (s, 3H), 2.73 (s, 3H); LC-MS: Method H, RT=0.88min, MS (ESI) m/z: 291.2 (M+H)⁺. Analytical HPLC Method B: 97.2% purity.

Example 131 5-(benzofuran-2-yl)-7-methyl-2-vinylquinoxaline

Intermediate 131A: 2-(benzyloxy)-5-iodo-7-methylquinoxaline

Intermediate I-14 (200 mg, 0.699 mmol) was suspended in toluene (4661μL). Silver oxide (405 mg, 1.748 mmol) then benzyl bromide (83 μL, 0.699mmol) were added and the reaction mixture was stirred for 1 week. Thereaction mixture was filtered to remove the silver salts andconcentrated in vacuo. The material was purified by columnchromatography (ISCO, 12 g silica gel column, 15 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate 131A (78.8 mg, 0.209mmol, 30%) as an off-white solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.47(s, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.64 (d, J=0.8 Hz, 1H), 7.52 (d, J=6.8Hz, 2H), 7.45-7.32 (m, 3H), 5.54 (s, 2H), 2.52 (s, 3H); LC-MS: Method H,RT=1.22 min, MS (ESI) m/z: 377.0 (M+H)⁺.

Intermediate 131B: 5-(benzofuran-2-yl)-2-(benzyloxy)-7-methylquinoxaline

Intermediate 131A (78.8 mg, 0.209 mmol) and benzofuran-2-ylboronic acid(50.9 mg, 0.314 mmol) were dissolved in toluene (1571 μL) and EtOH (524μL). PdCl₂(dppf)-CH₂Cl₂ (10.26 mg, 0.013 mmol) was added and thereaction mixture was degassed by bubbling with argon for 15 minutes.Sodium carbonate (2 M, 126 μL, 0.251 mmol) was added and the reactionmixture was degassed for 5 minutes, then sealed and heated to 90° C. inthe microwave for 30 minutes. The reaction mixture was diluted withEtOAc and filtered through a micron filter and concentrated in vacuo.The crude material was purified by column chromatography (ISCO, 12 gsilica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes)to give Intermediate 131B (67.7 mg, 0.185 mmol, 88%) as a yellow solid:¹H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (s, 1H), 8.15 (d, J=2.0 Hz, 1H),8.08 (d, J=0.8 Hz, 1H), 7.69-7.63 (m, 2H), 7.58-7.53 (m, 3H), 7.45-7.40(m, 2H), 7.39-7.28 (m, 3H), 5.56 (s, 2H), 2.63 (s, 3H); LC-MS: Method H,compound did not ionize.

Intermediate 131C:5-(benzofuran-2-yl)-7-methyl-3,4-dihydroquinoxalin-2(1H)-one

Intermediate 131B (67.7 mg, 0.185 mmol) was partially dissolved in MeOH(1848 μL) and EtOAc (1848 μL). Palladium on carbon (19.66 mg, 0.018mmol) was added. The reaction mixture was purged with hydrogen for 5minutes and sealed under a hydrogen balloon for 2.5 hours. The reactionmixture was diluted with EtOAc, filtered through a micron filter, andconcentrated in vacuo to give Intermediate 131C, which was used directlyin the subsequent step: LC-MS: Method H, RT=0.97 min, MS (ESI) m/z:279.1 (M+H)⁺.

Intermediate 131D: 5-(benzofuran-2-yl)-7-methylquinoxalin-2(1H)-one

Intermediate 131C (51 mg, 0.183 mmol) was suspended in MeOH (533 μL).NaOH (550 μL, 0.550 mmol) then H₂O₂ (96 μL, 1.100 mmol) were added andthe reaction mixture was stirred for 18 hours. More H₂O₂ (96 μL, 1.100mmol) was added and the reaction mixture was stirred for 24 hours. Thereaction mixture was diluted with water and extracted with EtOAc. Theorganic layer was further washed with brine, dried (Na₂SO₄), filtered,and concentrated in vacuo to give Intermediate 131D (34.6 mg, 0.125mmol, 68.3%) as a yellow solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 10.41(br. s., 1H), 8.40 (s, 1H), 7.98 (d, J=1.0 Hz, 1H), 7.92 (d, J=1.3 Hz,1H), 7.67 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.37-7.32 (m, 2H),7.00 (s, 1H), 2.57 (s, 3H); LC-MS: Method H, RT=1.01 min, MS (ESI) m/z:277.3 (M+H)⁺.

Intermediate 131E: 5-(benzofuran-2-yl)-7-methylquinoxalin-2-yltrifluoromethanesulfonate

Intermediate 131D (26 mg, 0.094 mmol), pyridine (19.03 μL, 0.235 mmol),and DIEA (36.2 μL, 0.207 mmol) were dissolved in DCM (4705 μL). Triflicanhydride (31.8 μL, 0.188 mmol) was added and the reaction mixture wasstirred for 2 hours. The reaction mixture was concentrated in vacuo. Thereaction mixture was filtered through a pad of silica gel in a frittedfunnel with rapid DCM elution to give Intermediate 131E (24.8 mg, 0.061mmol, 64.5%) as an orange solid: LC-MS: Method H, RT=1.28 min, MS (ESI)m/z: 409.0 (M+H)⁺.

Example 131

Intermediate 131E (24.8 mg, 0.061 mmol) and vinylboronic acid pinacolester (21.09 μL, 0.121 mmol) were dissolved in toluene (455 μL) and EtOH(152 μL). PdCl₂(dppf)-CH₂Cl₂ (2.98 mg, 3.64 μmol) was added and thereaction mixture was degassed by bubbling with argon for 15 minutes.Sodium carbonate (2 M, 36.4 μL, 0.073 mmol) was added and the reactionmixture was degassed for 5 minutes, then sealed and heated to 90° C. inthe microwave for 30 minutes. The reaction mixture was diluted withEtOAc and filtered through a micron filter and concentrated in vacuo.The crude material was purified by preparative HPLC (Method D, 45-75% Bin 10 minutes) to give Example 131 (2.6 mg, 0.00874 mmol, 14%): ¹H NMR(500 MHz, METHANOL-d₄) δ 9.11 (s, 1H), 8.28 (d, J=1.7 Hz, 1H), 8.11 (s,1H), 7.77 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.33(t, J=7.2 Hz, 1H), 7.27-7.21 (m, 1H), 7.05 (dd, J=17.9, 11.0 Hz, 1H),6.51 (d, J=17.9 Hz, 1H), 5.85 (d, J=11.3 Hz, 1H), 2.66 (s, 3H); LC-MS:Method H, RT=1.24 min, MS (ESI) m/z: 287.2 (M+H)⁺. Analytical HPLCMethod B: 97.3% purity.

Example 132 5-(benzofuran-2-yl)-2-ethyl-7-methylquinoxaline

Example 131 (1.4 mg, 4.89 μmol) (92793-013-01) was dissolved in MeOH(244 μL). Palladium on carbon (0.520 mg, 0.489 μmol) was added and thereaction mixture was sealed under an atmosphere of hydrogen for 30minutes. The reaction mixture was filtered and concentrated in vacuo.The crude material was purified by preparative HPLC (Method A, 30 to100% B in 20 minutes; with a flow rate of 40 mL/min). The desiredfractions were concentrated and lyophilized to give Example 132 (0.69mg, 0.00235 mmol, 48.2% yield) as a yellow solid: ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.87 (s, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.15 (d, J=0.8 Hz,1H), 7.85 (d, J=0.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.60-7.55 (m, 1H),7.37-7.31 (m, 1H), 7.29-7.23 (m, 1H), 3.12 (q, J=7.7 Hz, 2H), 2.67 (s,3H), 1.47 (t, J=7.7 Hz, 3H); LC-MS: Method H, RT=1.25 min, MS (ESI) m/z:289.2 (M+H)⁺. Analytical HPLC Method A: 98.4% purity.

Example 133 5-(benzofuran-2-yl)-2-(difluoromethoxy)-8-methylquinoxaline

Intermediate 133A: 6-bromo-3-methyl-2-nitroaniline

3-Methyl-2-nitroaniline (250 mg, 1.643 mmol) and NBS (292 mg, 1.643mmol) were dissolved in AcOH (8216 μL) and heated to 120° C. for 4hours. The reaction mixture was cooled to ambient temperature anddiluted with H₂O (50 mL). The material was extracted with EtOAc. Theorganic layer was washed twice with saturated NaHCO₃, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 40 g silica gel column, 19minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate133A (302.8 mg, 1.311 mmol, 80%) as an orange solid: ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.43 (d, J=9.0 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 4.77(br. s., 2H), 2.47 (s, 3H); LC-MS: Method H, RT=0.94 min, MS (ESI) m/z:231/233 (M+H)⁺.

Intermediate 133B: 3-bromo-6-methylbenzene-1,2-diamine

Intermediate 133A (302.8 mg, 1.311 mmol) was dissolved in MeOH (8961 μL)and THF (1120 μL). Ammonium chloride (1402 mg, 26.2 mmol) and zinc (857mg, 13.11 mmol) were added and the reaction mixture was heated to 40° C.for 1 hour. The reaction mixture was cooled to ambient temperature andconcentrated in vacuo. The crude material was redissolved inEtOAc/saturated Sodium carbonate and allowed to stir vigorously for 15minutes. The mixture was filtered through a sintered glass funnel. Theorganic layer was washed twice with water then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate 133B (257.8 mg,1.282 mmol, 98%): ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.91 (d, J=8.2 Hz,1H), 6.49 (d, J=8.8 Hz, 1H), 3.53 (br. s., 2H), 3.29 (br. s., 2H), 2.30(s, 3H); LC-MS: Method H, RT=0.54 min, MS (ESI) m/z: 201/203 (M+H)⁺.

Intermediate 133C: 3-(benzofuran-2-yl)-6-methylbenzene-1,2-diamine

Intermediate 133B (257.8 mg, 1.282 mmol) and benzofuran-2-ylboronic acid(311 mg, 1.923 mmol) were dissolved in toluene (9616 μL) and EtOH (3205μL). PdCl₂(dppf)-CH₂Cl₂ (62.8 mg, 0.077 mmol) was added and the reactionmixture was degassed by bubbling with argon for 15 minutes. Sodiumcarbonate (2 M, 769 μL, 1.539 mmol) was added and the reaction mixturewas degassed for 5 minutes, then sealed and heated to 90° C. in themicrowave for 60 minutes. The reaction mixture was diluted with EtOAcand filtered through a micron filter and concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 40 g silicagel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 133C (237.8 mg, 0.998 mmol, 78%) as a brown oil: ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.59-7.55 (m, 1H), 7.52-7.47 (m, 1H),7.29-7.18 (m, 2H), 7.10 (d, J=8.3 Hz, 1H), 6.73-6.65 (m, 2H), 3.51 (br.s., 4H), 2.36 (s, 3H); LC-MS: Method H, The compound did not ionize.

Intermediate 133D: 5-(benzofuran-2-yl)-8-methylquinoxalin-2(1H)-one

Intermediate 133C (237.8 mg, 0.998 mmol) was dissolved in EtOH (2697μL). Ethyl glyoxalate solution (50 wt %, 297 μL, 1.497 mmol) was addedand the reaction mixture was heated to 80° C. and allowed to stirovernight. The reaction mixture was cooled to ambient temperature andfiltered to collect the solid precipitate, which was washed with EtOHand collected to give Intermediate 133D (63.8 mg, 0.231 mmol, 23.1%) asan off-white solid mixture of regioisomers. The material was used as-isfor the subsequent step: LC-MS: Method H, RT=0.94 min, MS (ESI) m/z:277.1 (M+H)⁺.

Example 133

Intermediate 133D (30 mg, 0.109 mmol) and K₂CO₃ (300 mg, 2.172 mmol)were dissolved in DMF (1086 μL) and heated to 100° C. for 5 min. Sodium2-chloro-2,2-difluoroacetate (66.2 mg, 0.434 mmol) was added and thereaction mixture was heated for 2.5 hours. The reaction mixture wasdiluted with water and extracted thrice with DCM. The combined organicextracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by preparativeHPLC (Method D, 60 to 90% B in 25 minutes) then repurified bypreparative HPLC (Method D, 55-80% B in 15 minutes) to give Example 133(1.4 mg, 0.00417 mmol, 3.84%): ¹H NMR (500 MHz, METHANOL-d₄) δ 8.62 (s,1H), 8.24 (d, J=8.8 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.91-7.59 (m, 3H),7.36 (t, J=7.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.19 (s, 1H), 2.97 (s, 3H);LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 327.1 (M+H)⁺. AnalyticalHPLC Method B: 97.3% purity.

Example 134 8-(benzofuran-2-yl)-3-methoxy-6-methyl-1,7-naphthyridine\

Intermediate 134A: 5-methoxy-3-methylpicolinonitrile

5-Hydroxy-3-methylpicolinonitrile (0.25 g, 1.864 mmol) was suspended inDMF (12.43 mL). Cesium carbonate (1.518 g, 4.66 mmol) then iodomethane(0.146 mL, 2.330 mmol) were added and stirred for 3 hours. The reactionmixture was diluted with water and extracted with EtOAc. The organiclayer was washed with brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to give Intermediate 134A (252.7 mg, 1.706 mmol, 92%) as alight brown solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d, J=2.5 Hz,1H), 7.07 (d, J=2.8 Hz, 1H), 3.91 (s, 3H), 2.54 (s, 3H); LC-MS: MethodH, RT=0.71 min, MS (ESI) m/z: 149.2 (M+H)⁺.

Intermediate 134B: 5-methoxy-3-(2-oxopropyl)picolinonitrile

Intermediate 134A (252.7 mg, 1.706 mmol) was dissolved in DMF (1706 μL)and N,N-dimethylacetamide dimethyl acetal (1247 μL, 8.53 mmol) andheated to 150° C. for 18 hours. More N,N-dimethylacetamidedimethylacetal (0.5 mL) was added and heating continued for 24 hours.The reaction mixture was cooled to ambient temperature and concentratedin vacuo. The crude material was purified by preparative HPLC (Method A,20 to 100% B in 17 minutes) to give Intermediate 134B (81.8 mg, 0.430mmol, 25.2%) as a brown oil: ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.30 (d,J=2.8 Hz, 1H), 7.11 (d, J=2.8 Hz, 1H), 3.98 (s, 2H), 3.92 (s, 3H), 2.35(s, 3H); LC-MS: Method H, RT=0.64 min, MS (ESI) m/z: 191.2 (M+H)⁺.

Intermediate 134C: 3-methoxy-6-methyl-1,7-naphthyridin-8-ol

Intermediate 134B (81.8 mg, 0.430 mmol) was dissolved in CHCl₃ (3226μL), AcOH (538 μL), and HBr (538 μL) at and stirred overnight. Thereaction mixture was diluted with 1 N NaOH and extracted thrice withEtOAc. The combined organic layers were washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by preparative HPLC (Method A, 20 to 100% B in 17 minutes) togive Intermediate 134C (7.6 mg, 0.040 mmol, 9.3%) as a brown solid: ¹HNMR (400 MHz, METHANOL-d₄) δ 8.34 (d, J=8.8 Hz, 1H), 6.80 (d, J=8.8 Hz,1H), 6.44 (br. s., 1H), 4.02 (d, J=2.8 Hz, 3H), 2.33 (s, 3H); LC-MS:Method H, RT=0.55 min, MS (ESI) m/z: 191.2 (M+H)⁺.

Intermediate 134D:3-methoxy-6-methyl-1,7-naphthyridin-8-yltrifluoromethanesulfonate

Intermediate 134C (10.1 mg, 0.053 mmol), pyridine (21.47 μL, 0.266mmol), and DIEA (20.40 μL, 0.117 mmol) were dissolved in DCM (2655 μL).Triflic anhydride (35.9 μL, 0.212 mmol) was added and the reactionmixture was stirred for 45 minutes. More triflic anhydride (35.9 μL,0.212 mmol) was added and stirring continued for 30 minutes. Thereaction mixture was filtered through a pad of silica gel in a frittedfunnel with rapid DCM elution to give Intermediate 134D (11.8 mg, 0.037mmol, 69%) as a red oil: LC-MS: Method H, RT=1.01 min, MS (ESI) m/z:323.0 (M+H)⁺.

Example 134

Intermediate 134D (11.8 mg, 0.037 mmol) and benzofuran-2-ylboronic acid(7.12 mg, 0.044 mmol) were dissolved in DMF (366 μL). PdCl₂(dppf)-CH₂Cl₂(1.794 mg, 2.197 μmol) was added and the reaction mixture was degassedby bubbling with argon for 15 minutes. Sodium carbonate (2 M, 21.97 μL,0.044 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was diluted with EtOAc and filteredthrough a micron filter and concentrated in vacuo. The crude materialwas purified by preparative HPLC (Method D, 0 to 40% B in 10 minutes) togive Example 134 (2.0 mg, 0.00675 mmol, 18.4%): ¹H NMR (500 MHz,METHANOL-d₄) δ 8.82 (d, J=2.8 Hz, 1H), 8.57 (s, 1H), 7.79 (d, J=8.0 Hz,1H), 7.69 (d, J=8.3 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J=2.8 Hz, 1H), 7.47(t, J=7.7 Hz, 1H), 7.37-7.30 (m, 1H), 4.07 (s, 3H), 2.82 (s, 3H); LC-MS:Method H, RT=0.78 min, MS (ESI) m/z: 291.1 (M+H)⁺. Analytical HPLCMethod B: 98% purity.

Example 135 5-(benzofuran-2-yl)-2-(furan-3-yl)-7-methylquinoxaline

Intermediate 135A: 5-bromo-7-methylquinoxalin-2-yltrifluoromethanesulfonate

Intermediate I-1F (0.2 g, 0.837 mmol), pyridine (0.338 mL, 4.18 mmol),and DIEA (0.321 mL, 1.840 mmol) were dissolved in DCM (41.8 mL). Triflicanhydride (0.565 mL, 3.35 mmol) was added and the reaction mixture wasstirred for 1.5 hours. The reaction mixture was concentrated in vacuo.The reaction mixture was filtered through a pad of silica gel in afritted funnel with rapid DCM elution to give Intermediate 135A (137.3mg, 0.370 mmol, 44.2%) as a red oil: ¹H NMR (400 MHz, CHLOROFORM-d) δ8.78 (s, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.83 (s, 1H), 2.62 (s, 3H); LC-MS:Method H, RT=1.10 min, The compound did not ionize.

Intermediate 135B: 5-bromo-2-(furan-3-yl)-7-methylquinoxaline

Intermediate 135A (34.3 mg, 0.092 mmol) and furan-3-ylboronic acid(10.34 mg, 0.092 mmol) were dissolved in DMF (924 μL).PdCl₂(dppf)-CH₂Cl₂ (4.53 mg, 5.55 μmol) was added and the reactionmixture was degassed by bubbling with argon for 15 minutes. Sodiumcarbonate (2 M, 55.5 μL, 0.111 mmol) was added and the reaction mixturewas degassed for 5 minutes, then sealed and heated to 90° C. in themicrowave for 30 minutes. The reaction mixture was diluted with EtOAcand filtered through a micron filter and concentrated in vacuo. Thecrude material was purified by preparative HPLC (Method A, 20 to 100% Bin 15 minutes), to give Intermediate 135B (2.9 mg, 0.010 mmol, 10.9%) asa brown solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.07 (s, 1H), 8.24 (s,1H), 7.87 (d, J=1.5 Hz, 1H), 7.83 (s, 1H), 7.59 (t, J=1.6 Hz, 1H),7.15-7.11 (m, 1H), 2.58 (s, 3H); LC-MS: Method H, The compound did notionize.

Example 135

Intermediate 135B (2.9 mg, 10.03 μmol) and benzofuran-2-ylboronic acid(2.437 mg, 0.015 mmol) were dissolved in toluene (752 μL) and EtOH (251μL). PdCl₂(dppf)-CH₂Cl₂ (0.491 mg, 0.602 μmol) was added and thereaction mixture was degassed by bubbling with argon for 15 minutes.Sodium carbonate (2 M, 6.02 μL, 0.012 mmol) was added and the reactionmixture was degassed for 5 minutes, then sealed and heated to 90° C. inthe microwave for 30 minutes. The reaction mixture was diluted withEtOAc and filtered through a micron filter and concentrated in vacuo.The crude material was purified by preparative HPLC (Method D, 55 to 90%B in 10 minutes) to give 135 (1.1 mg, 0.0032 mmol, 31.9%): ¹H NMR (500MHz, METHANOL-d₄) δ 9.19 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.13 (s,1H), 7.82 (s, 1H), 7.71-7.64 (m, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.33 (t,J=7.6 Hz, 1H), 7.28-7.23 (m, 1H), 7.20 (s, 1H), 2.67 (s, 3H); LC-MS:Method H, RT=1.28 min, MS (ESI) m/z: 327.1 (M+H)⁺. Analytical HPLCMethod B: 95% purity.

Example 1362-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole

Intermediate 136A: 2-bromo-5,6-dihydro-4H-cyclopenta[d]thiazole

5,6-Dihydro-4H-cyclopenta[d]thiazol-2-amine, HCl (50 mg, 0.283 mmol) andisoamyl nitrite (41.9 μL, 0.311 mmol) were dissolved in MeCN (1132 μL).Copper(II) bromide (60.9 mg, 0.425 mmol) was added portionwise over 1hour. After an additional hour, the reaction mixture was diluted withwater and extracted with DCM. The DCM layer was washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate 136A,which was volatile and was used as-is for the next reaction: LC-MS:Method H, RT=0.99 min, MS (ESI) m/z: 204/206 (M+H)⁺.

Example 136

Intermediate I-1 (15 mg, 0.045 mmol) and Intermediate 136A (13.66 mg,0.067 mmol) were dissolved in DMF (446 μL). PdCl₂(dppf)-CH₂Cl₂ (2.187mg, 2.68 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 26.8 μL,0.054 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. More PdCl₂(dppf)-CH₂Cl₂ (2.187 mg, 2.68 μmol) and Sodiumcarbonate (2 M, 26.8 μL, 0.054 mmol) were added and the reaction mixturewas heated to 120° C. in the microwave for 30 minutes. The compound wasdiluted with DMF, filtered, and purified by preparative HPLC (Method D,35 to 80% B in 10 minutes) then repurified by preparative HPLC (MethodD, 45 to 80% B in 20 minutes) to give Example 136 (1.4 mg, 0.00403 mmol,9.0%): ¹H NMR (500 MHz, METHANOL-d₄) δ 8.64 (s, 1H), 8.42 (d, J=1.9 Hz,1H), 7.83-7.51 (m, 2H), 3.03 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.4 Hz, 2H),2.63 (s, 3H), 2.62-2.53 (m, 2H); LC-MS: Method H, RT=1.21 min, MS (ESI)m/z: 333.9 (M+H)⁺; Analytical HPLC Method B: 96% purity.

Example 1372-(2-methoxy-7-methylquinoxalin-5-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazole

Intermediate I-12 (10 mg, 0.043 mmol) and 2-chlorocycloheptanone (6.28mg, 0.043 mmol) were dissolved in dioxane (857 μL) and heated to 80° C.for 18 hours. More 2-chlorocycloheptanone (6.28 mg, 0.043 mmol) wasadded and the reaction mixture was heated to 110° C. for 24 hours. Thereaction mixture was concentrated in vacuo, diluted with DMF, filtered,and purified by preparative HPLC (Method D, 55 to 95% B in 10 minutes)to give Example 137 (2.9 mg, 0.00873 mmol, 20.4%): ¹H NMR (500 MHz,METHANOL-d₄) δ 8.48 (s, 1H), 8.26 (d, J=1.7 Hz, 1H), 7.66 (s, 1H), 4.11(s, 3H), 3.08-3.01 (m, 2H), 2.95-2.89 (m, 2H), 2.60 (s, 3H), 1.98-1.87(m, 2H), 1.83-1.71 (m, 4H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z:326.1 (M+H)⁺; Analytical HPLC Method B: 98% purity.

Example 1382-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol

Intermediate 138A2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6-dihydrobenzo[d]thiazol-7(4H)-one

Intermediate I-12 (15 mg, 0.064 mmol) and 2-chlorocyclohexane-1,3-dione(18.85 mg, 0.129 mmol) were dissolved in 1,4-dioxane (1286 μL) andheated to 100° C. for 18 hours. The reaction mixture was concentrated invacuo, diluted with DMF, filtered, and purified by preparative HPLC(Method D, 35 to 75% B in 10 minutes) to give Intermediate 138A (4.6 mg,0.014 mmol, 21.6%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.53 (s,1H), 7.86 (s, 1H), 4.08 (s, 3H), 3.10 (t, J=6.1 Hz, 2H), 2.67-2.58 (m,5H), 2.24-2.15 (m, 2H); LC-MS: Method H, RT=1.12 min, MS (ESI) m/z:326.1 (M+H)⁺; Analytical HPLC Method B: 98% purity.

Example 138

Intermediate 138A (3.68 mg, 0.011 mmol) was dissolved in MeOH (565 μL)and cooled to 0° C. Sodium borohydride (0.642 mg, 0.017 mmol) was addedand the reaction mixture was allowed to slowly warm to ambienttemperature and stir for 20 hours. The reaction mixture was diluted withwater and extracted with EtOAc. The organic layer was washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude materialwas diluted with DMF, filtered, and purified by preparative HPLC (MethodD, 25 to 65% B in 10 minutes) to give Example 138 (2.3 mg, 0.00703 mmol,62.1%): ¹H NMR (500 MHz, METHANOL-d₄) δ 8.49 (s, 1H), 8.30 (d, J=1.7 Hz,1H), 7.70 (d, J=0.8 Hz, 1H), 5.03 (br. s., 1H), 4.24 (br. s., 1H), 4.11(s, 3H), 2.96-2.88 (m, 1H), 2.87-2.78 (m, 1H), 2.61 (s, 3H), 2.13 (d,J=9.9 Hz, 2H), 1.95-1.86 (m, 2H); LC-MS: Method H, RT=0.94 min, MS (ESI)m/z: 328.2 (M+H)⁺; Analytical HPLC Method B: 100% purity.

Example 1397-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole

Example 138 (9.9 mg, 0.030 mmol) was dissolved in THF (605 μL). Sodiumhydride (1.330 mg, 0.033 mmol) was added and the reaction mixture wasstirred for 30 minutes. Iodomethane (3.78 μL, 0.060 mmol) was added andthe reaction mixture was stirred for 2 hours. The reaction mixture wasdiluted with EtOAc and washed with water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was diluted withDMF, filtered, and purified by preparative HPLC (Method D, 40 to 80% Bin 10 minutes) to give Example 139 (6.4 mg, 0.018 mmol, 60.8%): ¹H NMR(500 MHz, METHANOL-d₄) δ 8.51 (s, 1H), 8.33 (d, J=1.7 Hz, 1H), 7.71 (dd,J=1.9, 0.8 Hz, 1H), 7.62 (dd, J=3.0, 1.7 Hz, 1H), 4.12 (s, 3H), 3.54 (s,3H), 3.00-2.90 (m, 1H), 2.87-2.78 (m, 1H), 2.61 (s, 3H), 2.16-2.00 (m,3H), 1.96-1.86 (m, 1H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z:342.2 (M+H)⁺; Analytical HPLC Method B: 98% purity.

Example 1406-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole

Intermediate 140A: 4-((tert-butyldimethylsilyl)oxy)cyclohexanone

4-hydroxycyclohexanone (500 mg, 4.38 mmol), TBS-Cl (792 mg, 5.26 mmol),and imidazole (447 mg, 6.57 mmol) were dissolved in DCM (8761 μL) for 3hours. The reaction mixture was diluted with DCM, washed with water, 1 NHCl, saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 140A as a light yellow oil:¹H NMR (400 MHz, CHLOROFORM-d) δ 4.09 (tt, J=5.1, 2.7 Hz, 1H), 2.69-2.56(m, 2H), 2.24-2.14 (m, 2H), 1.99-1.77 (m, 4H), 0.88 (s, 9H), 0.06 (s,6H).

Intermediate 140B2-(2-methoxy-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-ol

Intermediate 140A (9.79 mg, 0.043 mmol), magnesium chloride (4.08 mg,0.043 mmol), and NBS (7.63 mg, 0.043 mmol) were dissolved in dioxane(429 μL) and heated to 70° C. for 1 hour. Intermediate I-12 (10 mg,0.043 mmol) was added and the reaction mixture was stirred for 18 hours.The reaction mixture was heated to 110° C. for 4 hours. The reactionmixture was diluted with EtOAc, washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material wasdissolved in 90:10:0.1 MeOH:H₂O:TFA (ca 1 mL) and allowed to stirovernight. The reaction mixture was concentrated in vacuo. The crudematerial was dissolved in DMF, filtered, and purified by preparativeHPLC (Method D, 20 to 60% B in 10 minutes) to give Intermediate 140B(2.7 mg, 0.00825 mmol, 19.2%): ¹H NMR (500 MHz, METHANOL-d₄) δ 8.48 (s,1H), 8.27 (d, J=1.9 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H), 4.26-4.19 (m, 1H),4.11 (s, 3H), 3.18 (dd, J=16.1, 4.8 Hz, 1H), 3.09-3.00 (m, 1H),2.95-2.87 (m, 1H), 2.83 (dd, J=16.2, 7.2 Hz, 1H), 2.61 (s, 3H),2.17-2.09 (m, 1H), 2.04-1.95 (m, 1H); LC-MS: Method H, RT=0.95 min, MS(ESI) m/z: 328.3 (M+H)⁺; Analytical HPLC Method B: 100% purity.

Example 140

Intermediate 140B (1.78 mg, 5.44 μmol) was dissolved in THF (109 μL).Sodium hydride (0.239 mg, 5.98 μmol) was added and the reaction mixturewas stirred for 30 minutes. Iodomethane (0.680 μL, 10.87 μmol) was addedand the reaction mixture was stirred for 2 hours. The reaction mixturewas diluted with EtOAc and washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material wasdiluted with DMF, filtered, and purified by preparative HPLC (Method D,45 to 90% B in 10 minutes) to give Example 140 (0.9 mg, 0.00264 mmol,48.5%): ¹H NMR (500 MHz, METHANOL-d₄) δ 8.48 (s, 1H), 8.27 (d, J=1.9 Hz,1H), 7.68 (d, J=0.8 Hz, 1H), 4.11 (s, 3H), 3.88-3.82 (m, 1H), 3.20 (dd,J=16.4, 5.4 Hz, 1H), 3.06-2.97 (m, 1H), 2.94-2.86 (m, 2H), 2.61 (s, 3H),2.18-2.03 (m, 2H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 342.2(M+H)⁺; Analytical HPLC Method B: 100% purity.

Example 1412-(2-methoxy-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazole

4,4-Dimethylcyclohexanone (6.49 mg, 0.051 mmol), magnesium chloride(4.08 mg, 0.043 mmol), and NBS (9.16 mg, 0.051 mmol) were dissolved indioxane (429 μL) and heated to 70° C. for 1 hour. Intermediate I-12 (10mg, 0.043 mmol) was added and the reaction mixture was heated to 110° C.for 18 hours. The reaction mixture was diluted with EtOAc, washed withwater, then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude material was dissolved in DMF, filtered, and purified bypreparative HPLC (Method D, 55 to 100% B in 10 minutes) to give Example141 (3.3 mg, 0.00943 mmol, 22%): ¹H NMR (500 MHz, METHANOL-d₄) δ 8.48(s, 1H), 8.27 (d, J=1.9 Hz, 1H), 7.68 (dd, J=1.9, 0.8 Hz, 1H), 4.11 (s,3H), 2.88 (t, J=6.6 Hz, 2H), 2.66 (s, 2H), 2.61 (s, 3H), 1.72 (t, J=6.5Hz, 2H), 1.08 (s, 6H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 340.0(M+H)⁺; Analytical HPLC Method B: 97% purity.

Example 1422-(2-(2-methoxy-7-methylquinoxalin-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazol-5-yl)ethanol

Intermediate 142A:3-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopentanone

3-(2-hydroxyethyl)cyclopentanone (500 mg, 3.90 mmol), TBS-Cl (706 mg,4.68 mmol), and imidazole (398 mg, 5.85 mmol) were dissolved in DCM(7802 μL) for 3.5 hours. The reaction mixture was diluted with DCM,washed with water, 1 N HCl, saturated NaHCO₃, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate 142Aas a light yellow oil: ¹H NMR (400 MHz, CHLOROFORM-d) δ 3.63-3.52 (m,2H), 2.35-2.26 (m, 1H), 2.25-2.13 (m, 2H), 2.12-1.99 (m, 2H), 1.73 (ddd,J=17.9, 10.0, 1.3 Hz, 1H), 1.65-1.40 (m, 3H), 0.80 (s, 9H), −0.05 (s,6H).

Example 142

Intermediate 142A (18.71 mg, 0.077 mmol), magnesium chloride (6.12 mg,0.064 mmol), and NBS (13.73 mg, 0.077 mmol) were dissolved in dioxane(643 μL) and heated to 70° C. for 1 hour.2-Methoxy-7-methylquinoxaline-5-carbothioamide (15 mg, 0.064 mmol) wasadded and the reaction mixture was heated to 110° C. for 18 hours. Thereaction mixture was diluted with EtOAc, washed with water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude materialwas dissolved in 90:10:0.1 MeOH:H₂O:TFA (ca 1 mL) for 18 hours. Thereaction mixture was concentrated in vacuo. The crude material wasdissolved in DMF, filtered, and purified by preparative HPLC (Method D,35 to 80% B in 10 minutes) to give Example 142 (2.9 mg, 0.00790 mmol,12.3%): LC-MS: Method H, RT=1.04 min, MS (ESI) m/z: 342.0 (M+H)⁺;Analytical HPLC Method B: 93% purity.

Example 1432-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol

Intermediate 143A: 2-amino-5,6-dihydrobenzo[d]thiazol-7(4H)-one, HCl

2-chlorocyclohexane-1,3-dione (1 g, 6.82 mmol) and thiourea (0.519 g,6.82 mmol) were dissolved in EtOH (13.65 mL) and heated to 80° C. for 3days. The reaction mixture was cooled to ambient temperature and thesolid collected by suction filtration, washing with EtOH to giveIntermediate 143A (790 mg, 3.86 mmol, 56.6%) as a white solid: ¹H NMR(400 MHz, METHANOL-d₄) δ 2.80 (t, J=6.2 Hz, 2H), 2.51 (dd, J=7.2, 5.8Hz, 2H), 2.15 (quin, J=6.4 Hz, 2H); LC-MS: Method H, RT=0.63 min, MS(ESI) m/z: 169.0 (M+H)⁺.

Intermediate 143B: 2-bromo-5,6-dihydrobenzo[d]thiazol-7(4H)-one

Copper(II) bromide (1.466 g, 6.56 mmol) and t-butyl nitrite (0.780 mL,6.56 mmol) were dissolved in MeCN (15.44 mL) and allowed to stir 10minutes. Intermediate 143A (0.79 g, 3.86 mmol) was dissolved in MeCN(23.16 mL) and the copper solution was added and the reaction mixturewas stirred for 1.5 hours. The reaction mixture was concentrated invacuo. The residue was dissolved in EtOAc, washed twice with 1 N HCl,saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to give Intermediate 143B (817.9 mg, 3.52 mmol, 91%) as anorange solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 3.07 (t, J=6.2 Hz, 2H),2.64 (dd, 5.7 Hz, 2H), 2.24 (quin, J=6.4 Hz, 2H); LC-MS: Method H,RT=0.98 min, MS (ESI) m/z: 232/234 (M+H)⁺.

Intermediate 143C: 2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol

Intermediate 143B (500 mg, 2.154 mmol) was dissolved in MeOH (10.8 mL)and cooled to 0° C. Sodium borohydride (163 mg, 4.31 mmol) was added andstirred for 1.5 hours. The reaction mixture was quenched with saturatedammonium chloride and extracted with EtOAc. The organic layer was washedwith water, then brine, dried (Na₂SO₄), filtered, and concentrated invacuo to give Intermediate 143C (488 mg, 2.084 mmol, 97%) as an orangeoil: ¹H NMR (400 MHz, CHLOROFORM-d) δ 4.93 (br. s., 1H), 2.89-2.79 (m,1H), 2.79-2.69 (m, 1H), 2.17-2.07 (m, 1H), 2.06-1.98 (m, 1H), 1.92-1.80(m, 2H); LC-MS: Method H, RT=0.88 min, MS (ESI) m/z: 234/236 (M+H)⁺.

Example 143

Intermediate I-2 was purified by column chromatography (ISCO, 12 gsilica gel column, 17 minute gradient from 0 to 20% MeOH in DCM) to givedimethyl (2-(methoxymethyl)-7-methylquinoxalin-5-yl)boronate (25 mg,0.096 mmol), Intermediate 143C (27.0 mg, 0.115 mmol), and potassiumphosphate tribasic (40.8 mg, 0.192 mmol) were dissolved in DMF (961 μL)and degassed by bubbling with argon for 15 minutes. Palladiumtetrakistriphenylphosphine (11.11 mg, 9.61 μmol) was added and degassingcontinued for 5 minutes. The reaction mixture was heated to 85° C. atfor 18 hours. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 20 to 60% B in 20 minutes) togive Example 143 (5.4 mg, 0.015 mmol, 15.1%): ¹H NMR (500 MHz, DMSO-d₆)δ 9.06 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H), 5.56 (d, J=6.3 Hz, 1H), 4.92(br. s., 1H), 4.80 (s, 2H), 3.47 (s, 3H), 2.87-2.73 (m, 2H), 2.65 (s,3H), 2.07-1.99 (m, 2H), 1.84-1.70 (m, 2H); LC-MS: Method H, RT=1.02 min,MS (ESI) m/z: 342.2 (M+H)⁺; Analytical HPLC Method B: 92% purity.

Example 1442-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole

Intermediate 144A:2-(tributylstannyl)-4,5,6,7-tetrahydrobenzo[d]thiazole

2-Bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (25 mg, 0.115 mmol) wasdissolved in Et₂O (458 μL) and cooled to −78° C. BuLi (60.0 μL, 0.126mmol) was added and the reaction mixture was stirred for 30 minutes.Tributylchlorostannane (31.1 μL, 0.115 mmol) was added and stirred for40 minutes. The reaction mixture was warmed to ambient temperature andconcentrated in vacuo. The crude material was suspended in hexanes andfiltered through dry celite. The residue was concentrated in vacuo togive Intermediate 144A, which was used directly in the subsequentreaction.

Example 144

Intermediate I-2E (15 mg, 0.056 mmol), Intermediate 144A (30.1 mg, 0.070mmol), and potassium acetate (11.02 mg, 0.112 mmol) were dissolved indioxane (814 μL) and degassed by bubbling with argon for 15 minutes.Palladium tetrakistriphenylphosphine (3.24 mg, 2.81 μmol) was added andthe reaction mixture was sealed and heated to 120° C. in the microwavefor 2 hours. The reaction mixture was diluted with EtOAc, washed withwater, 1 N HCl, then brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The crude material was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 40 to 80% B in 20 minutes) andrepurified by preparative HPLC (Method D, 50 to 85% B in 20 minutes) togive Example 144 (1.9 mg, 0.00584 mmol, 10.4%): ¹H NMR (500 MHz,DMSO-d₆) δ 9.03 (s, 1H), 8.59 (s, 1H), 7.92 (s, 1H), 4.79 (s, 2H), 3.46(s, 3H), 2.88 (br. s., 2H), 2.82 (br. s., 2H), 2.64 (s, 3H), 1.87 (br.s., 4H); LC-MS: Method H, RT=1.23 min, MS (ESI) m/z: 326.3 (M+H)⁺;Analytical HPLC Method B: 100% purity.

Example 1452-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol

Intermediate 145A:2-amino-6,6-dimethyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one, HCl

2-bromo-4,4-dimethylcyclohexane-1,3-dione (0.5 g, 2.282 mmol) andthiourea (0.174 g, 2.282 mmol) were dissolved in EtOH (4.56 mL) andheated to 75° C. for 18 hours. The reaction mixture was cooled toambient temperature then to 0° C. and the solid was collected by suctionfiltration, washing with cold EtOH to give Intermediate 145A (128.3 mg,0.551 mmol, 24.2%) as an off-white solid: ¹H NMR (400 MHz, METHANOL-d₄)δ 2.90 (t, J=6.2 Hz, 2H), 2.08 (t, J=6.2 Hz, 2H), 1.20 (s, 6H); LC-MS:Method H, RT=0.85 min, MS (ESI) m/z: 197.1 (M+H)⁺.

Intermediate 145B:2-bromo-6,6-dimethyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one

Copper(II) bromide (248 mg, 1.111 mmol) and t-butyl nitrite (132 μL,1.111 mmol) were dissolved in MeCN (2615 μL) and allowed to stir 10minutes. Intermediate 145A (128.3 mg, 0.654 mmol) was dissolved in MeCN(3922 μL) and the copper solution was added and stirring continued for1.5 hours. The reaction mixture was diluted with EtOAc, washed with 1 NHCl, saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 145B (110 mg, 0.423 mmol,64.7%): ¹H NMR (400 MHz, CHLOROFORM-d) δ 3.08 (t, J=6.2 Hz, 2H), 2.06(t, J=6.2 Hz, 2H), 1.25 (s, 6H); LC-MS: Method H, RT=1.21 min, MS (ESI)m/z: 260/262 (M+H)⁺.

Intermediate 145C:2-bromo-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ol

Intermediate 145B (110 mg, 0.423 mmol) was dissolved in MeOH (2114 μL)and cooled to 0° C. Sodium borohydride (32.0 mg, 0.846 mmol) was addedand the reaction mixture stirred for 40 minutes. The reaction mixturewas quenched with saturated ammonium chloride and extracted with EtOAc.The organic layer was washed with water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate 145C (107 mg,0.408 mmol, 97%) as a yellow oil: ¹H NMR (400 MHz, CHLOROFORM-d) δ 4.45(d, J=6.4 Hz, 1H), 2.88-2.68 (m, 2H), 1.93 (d, J=7.5 Hz, 1H), 1.82 (dt,J=13.8, 5.9 Hz, 1H), 1.70-1.63 (m, 1H), 1.07 (s, 3H), 1.02 (s, 3H);LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 263.9 (M+H)⁺.

Example 145

Intermediate I-2 was purified by column chromatography (ISCO, 12 gsilica gel column, 17 minute gradient from 0 to 20% MeOH in DCM) to givedimethyl (2-(methoxymethyl)-7-methylquinoxalin-5-yl)boronate (20 mg,0.077 mmol), Intermediate 145C (24.19 mg, 0.092 mmol), and potassiumphosphate tribasic (32.6 mg, 0.154 mmol) were dissolved in DMF (7694)and degassed by bubbling with argon for 15 minutes. Palladiumtetrakistriphenylphosphine (8.89 mg, 7.69 μmol) was added and degassingcontinued for 5 minutes. The reaction mixture was heated to 85° C. for18 hours. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 40 to 80% B in 20 minutes) togive Example 145 (5.6 mg, 0.015 mmol, 18.9%): ¹H NMR (500 MHz, DMSO-d₆)δ 9.06 (s, 1H), 8.60 (d, J=1.4 Hz, 1H), 7.94 (s, 1H), 5.58 (d, J=6.9 Hz,1H), 4.80 (s, 2H), 4.48 (d, J=6.3 Hz, 1H), 3.47 (s, 3H), 2.82-2.74 (m,2H), 2.65 (s, 3H), 1.86-1.78 (m, 1H), 1.70-1.62 (m, 1H), 1.03 (s, 3H),0.91 (s, 3H); LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 370.1 (M+H)⁺;Analytical HPLC Method B: 96% purity.

Example 1462-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine

Intermediate 146A: 2-bromothiazolo[4,5-c]pyridine

Copper(II) bromide (71.6 mg, 0.320 mmol) and t-butyl nitrite (38.1 μL,0.320 mmol) were dissolved in MeCN (754 μL) and allowed to stir 10minutes. Thiazolo[4,5-c]pyridin-2-amine, TFA (50 mg, 0.189 mmol) wasdissolved in MeCN (1131 μL) and the copper solution was added and thereaction mixture was stirred for 2 hours. The reaction mixture wasdiluted with EtOAc, washed with saturated NaHCO₃, water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate146A (12.5 mg, 0.058 mmol, 30.8%) as a brown solid: LC-MS: Method H,RT=0.68 min, MS (ESI) m/z: 215/217 (M+H)⁺.

Example 146

Intermediate I-2 (10 mg, 0.032 mmol) and Intermediate 146A (10.27 mg,0.048 mmol) were dissolved in DMF (318 μL). PdCl₂(dppf)-CH₂Cl₂ (1.560mg, 1.910 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 19.10 μL,0.038 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 25 to 65% B in 20 minutes) togive Example 146 (3.0 mg, 0.00893 mmol, 28.1%): ¹H NMR (500 MHz,DMSO-d₆) δ 9.43 (br. s., 1H), 9.14 (br. s., 1H), 8.92 (br. s., 1H), 8.57(br. s., 1H), 8.30 (br. s., 1H), 8.14 (br. s., 1H), 4.84 (br. s., 2H),3.49 (br. s., 3H), 2.72 (br. s., 3H); LC-MS: Method H, RT=0.90 min, MS(ESI) m/z: 323.3 (M+H)⁺; Analytical HPLC Method B: 96% purity.

Example 1472-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine

Intermediate 147A: 2-bromo-5-methoxythiazolo[5,4-b]pyridine

Copper(II) bromide (64.3 mg, 0.288 mmol) and t-butyl nitrite (34.2 μL,0.288 mmol) were dissolved in MeCN (677 μL) and allowed to stir 10minutes. 5-methoxythiazolo[5,4-b]pyridin-2-amine, TFA (50 mg, 0.169mmol) was dissolved in MeCN (1016 μL) and the copper solution was addedand the reaction mixture was stirred for 1.5 hours. The reaction mixturewas diluted with EtOAc, washed with saturated NaHCO₃, water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate147A as a tan solid: ¹H NMR (500 MHz, CHLOROFORM-d) δ 8.08 (d, J=8.8 Hz,1H), 6.86 (d, J=8.8 Hz, 1H), 4.02 (s, 3H); LC-MS: Method H, RT=1.21 min,MS (ESI) m/z: 245/247 (M+H)⁺.

Example 147

Intermediate I-2 (10 mg, 0.032 mmol) and Intermediate 147A (11.70 mg,0.048 mmol) were dissolved in DMF (318 μL). PdCl₂(dppf)-CH₂Cl₂ (1.560mg, 1.910 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 19.10 μL,0.038 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 45 to 85% B in 20 minutes) togive Example 147 (3.1 mg, 0.00862 mmol, 27.1%): ¹H NMR (500 MHz,DMSO-d₆) δ 9.14 (br. s., 1H), 8.81 (br. s., 1H), 8.43 (d, J=8.0 Hz, 1H),8.08 (br. s., 1H), 7.08 (d, J=8.8 Hz, 1H), 4.84 (br. s., 2H), 4.02 (br.s., 3H), 3.49 (br. s., 3H), 2.70 (br. s., 3H); LC-MS: Method H, RT=1.34min, MS (ESI) m/z: 353.2 (M+H)⁺; Analytical HPLC Method B: 98% purity.

Example 1482-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine

Intermediate I-2 (10 mg, 0.032 mmol) and 2-bromothiazolo[5,4-b]pyridine(10.27 mg, 0.048 mmol) (10.27 mg, 0.048 mmol) were dissolved in DMF (318μL). PdCl₂(dppf)-CH₂Cl₂ (1.560 mg, 1.910 μmol) was added and thereaction mixture was degassed by bubbling with argon for 15 minutes.Sodium carbonate (2 M, 19.10 μL, 0.038 mmol) was added and the reactionmixture was degassed for 5 minutes, then sealed and heated to 100° C. inthe microwave for 30 minutes. The reaction mixture was diluted with DMF,filtered, and purified by preparative HPLC (Method D, 30 to 70% B in 20minutes) to give Example 148 (3.0 mg, 0.00893 mmol, 28.1%): ¹H NMR (500MHz, DMSO-d₆) δ 9.17 (br. s., 1H), 8.89 (br. s., 1H), 8.70 (br. s., 1H),8.54 (d, J=8.3 Hz, 1H), 8.14 (br. s., 1H), 7.66 (br. s., 1H), 4.84 (br.s., 2H), 3.49 (br. s., 3H), 2.72 (br. s., 3H); LC-MS: Method H, RT=1.20min, MS (ESI) m/z: 323.2 (M+H)⁺; Analytical HPLC Method B: 96% purity.

Example 1497-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyridine

Intermediate I-2 (10 mg, 0.032 mmol) and2-bromo-7-chlorothiazolo[5,4-c]pyridine (11.91 mg, 0.048 mmol) weredissolved in DMF (318 μL). PdCl₂(dppf)-CH₂Cl₂ (1.560 mg, 1.910 μmol) wasadded and the reaction mixture was degassed by bubbling with argon for15 minutes. Sodium carbonate (2 M, 19.10 μL, 0.038 mmol) was added andthe reaction mixture was degassed for 5 minutes, then sealed and heatedto 100° C. in the microwave for 30 minutes. The reaction mixture wasdiluted with DMF, filtered, and purified by preparative HPLC (Method D,45 to 85% B in 12 minutes) to give Example 149 (3.1 mg, 0.00834 mmol,26.2%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.46 (s, 1H), 9.17 (s, 1H), 8.96 (d,J=1.9 Hz, 1H), 8.75 (s, 1H), 8.21 (s, 1H), 4.86 (s, 2H), 3.49 (s, 3H),2.75 (s, 3H); LC-MS: Method H, RT=1.28 min, MS (ESI) m/z: 357.1 (M+H)⁺;Analytical HPLC Method B: 96% purity.

Example 1505-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine

Intermediate I-9 (10 mg, 0.033 mmol),2-bromo-5-methoxythiazolo[5,4-b]pyridine (9.80 mg, 0.040 mmol), andpotassium phosphate tribasic (14.14 mg, 0.067 mmol) were dissolved inDMF (333 μL) and degassed by bubbling with argon for 15 minutes.Palladium tetrakistriphenylphosphine (3.85 mg, 3.33 μmol) was added anddegassing continued for 5 minutes. The reaction mixture was heated to85° C. for 18 hours. The reaction mixture was diluted with DMF,filtered, and purified by preparative HPLC (Method D, 60 to 100% B in 20minutes) to give Example 150 (1.1 mg, 0.00325 mmol, 9.8%): LC-MS: MethodH, RT=1.50 min, MS (ESI) m/z: 339.1 (M+H)⁺; Analytical HPLC Method B:100% purity.

Example 1517-chloro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-c]pyridine

Intermediate I-9 (10 mg, 0.033 mmol),2-bromo-7-chlorothiazolo[5,4-c]pyridine (9.98 mg, 0.040 mmol), andpotassium phosphate tribasic (14.14 mg, 0.067 mmol) were dissolved inDMF (333 μL) and degassed by bubbling with argon for 15 minutes.Palladium tetrakistriphenylphosphine (3.85 mg, 3.33 μmol) was added anddegassing continued for 5 minutes. The reaction mixture was heated to85° C. for 24 hours. The reaction mixture was diluted with DMF,filtered, and purified by preparative HPLC (Method D, 50 to 100% B in 20minutes) then repurified by preparative (Method D, 45 to 85% B in 20minutes) to give Example 151 (0.9 mg, 0.00252 mmol, 7.6%): ¹H NMR (500MHz, CHLOROFORM-d) δ 9.17 (br. s., 1H), 8.88 (br. s., 1H), 8.68 (br. s.,1H), 8.62 (br. s., 1H), 7.89 (br. s., 1H), 4.18 (br. s., 3H), 2.73 (br.s., 3H); LC-MS: Method H, RT=1.40 min, MS (ESI) m/z: 343.1 (M+H)⁺;Analytical HPLC Method B: 96% purity.

Example 152 methyl6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxylate

Intermediate I-9 (99 mg, 0.331 mmol), Intermediate I-20C (100 mg, 0.331mmol), and potassium phosphate tribasic (141 mg, 0.662 mmol) weredissolved in DMF (3310 μL) and degassed by bubbling with argon for 15minutes. Palladium tetrakistriphenylphosphine (38.2 mg, 0.033 mmol) wasadded and degassing continued for 5 minutes. The reaction mixture washeated to 85° C. for 18 hours. The reaction mixture was diluted withwater and extracted thrice with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude material was diluted with DMF, filtered, and purified bypreparative HPLC (Method D, 60 to 100% B in 15 minutes) to give Example152 (2.7 mg, 0.00676 mmol, 2%) as a yellow solid: ¹H NMR (500 MHz,DMSO-d₆) δ 8.77 (br. s., 1H), 8.61 (br. s., 1H), 8.04 (br. s., 1H), 7.87(br. s., 1H), 7.57 (br. s., 1H), 4.10 (br. s., 3H), 4.01 (br. s., 3H),3.93 (br. s., 3H), 2.67 (br. s., 3H); LC-MS: Method H, RT=1.40 min, MS(ESI) m/z: 396.1 (M+H)⁺; Analytical HPLC Method B: 99% purity.

Example 1536-methoxy-2-(3-(methoxymethyl)-6-methyl-1,7-naphthyridin-8-yl)-4-methylbenzo[d]thiazole

Intermediate 153A: 2-nitroacetamide

Ethyl 2-nitroacetate (1 g, 7.51 mmol) was dissolved in NH₃ in MeOH (7 M,16.10 mL, 113 mmol) and heated to 65° C. in a sealed tube at for 5hours. The reaction mixture was cooled to ambient temperature andconcentrated in vacuo to give Intermediate 153A, which was used directlyin the subsequent reaction.

Intermediate 153B: ethyl6-methyl-3-nitro-2-oxo-1,2-dihydropyridine-4-carboxylate

Intermediate 153A (782 mg, 7.51 mmol), ethyl 2,4-dioxovalerate (1161 μL,8.27 mmol), and piperidinium acetate (1091 mg, 7.51 mmol) were dissolvedin water (37.6 mL) and stirred for 18 hours. The reaction mixture wasconcentrated in vacuo. The crude material was dissolved in DCM, filteredand purified by column chromatography (ISCO, 80 g silica gel column, 29minute gradient from 0 to 20% MeOH in DCM) to give Intermediate 153B(890 mg, 3.93 mmol, 52.4%) as an orange solid: ¹H NMR (400 MHz,CHLOROFORM-d) δ 6.49 (d, J=0.7 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 2.49 (d,J=0.7 Hz, 3H), 1.38 (t, J=7.2 Hz, 3H); LC-MS: Method H, RT=0.90 min, MS(ESI) m/z: 227.2 (M+H)⁺.

Intermediate 153C: ethyl 2-(benzyloxy)-6-methyl-3-nitroisonicotinate

Intermediate 153B (400 mg, 1.768 mmol) was suspended in toluene (11.8mL). Silver oxide (1025 mg, 4.42 mmol) then benzyl bromide (210 μL,1.768 mmol) were added and the reaction mixture was heated to 40° C. for4 days. The reaction mixture was diluted with EtOAc and filtered througha micron filter. The residue was concentrated in vacuo. The crudematerial was purified by column chromatography (ISCO, 40 g silica gelcolumn, 29 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 153C (260 mg, 0.822 mmol, 46.5%) as a white solid: ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.49-7.30 (m, 5H), 7.22 (d, J=0.4 Hz, 1H),5.53 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.57 (d, J=0.4 Hz, 3H), 1.37 (t,J=7.2 Hz, 3H); LC-MS: Method H, RT=1.32 min, MS (ESI) m/z: 317.1 (M+H)⁺.

Intermediate 153D: (2-(benzyloxy)-6-methyl-3-nitropyridin-4-yl)methanol

Sodium borohydride (93 mg, 2.466 mmol) and calcium chloride (137 mg,1.233 mmol) were dissolved in THF (3288 μL). After 1 hour, a solution ofIntermediate 153C (260 mg, 0.822 mmol) in THF (822 μL) was addeddropwise. After 18 hours, the reaction mixture was diluted with EtOAc,washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 153D (169 mg, 0.616 mmol,75%) as a yellow oil: ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.49-7.44 (m,2H), 7.42-7.36 (m, 2H), 7.36-7.31 (m, 1H), 7.04 (s, 1H), 5.53 (s, 2H),4.75 (s, 2H), 2.54 (s, 3H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z:275.1 (M+H)⁺.

Intermediate 153E: (3-amino-2-(benzyloxy)-6-methylpyridin-4-yl)methanol

Intermediate 153D (169 mg, 0.616 mmol) was dissolved in MeOH (4213 μL)and THF (527 μL). Ammonium chloride (659 mg, 12.32 mmol) and zinc (403mg, 6.16 mmol) were added and the reaction mixture was heated to 40° C.for 1.5 hours. The reaction mixture was concentrated in vacuo. The crudematerial was redissolved in EtOAc/saturated sodium carbonate and allowedto stir vigorously for 15 minutes. The mixture was filtered through asintered glass funnel. The organic layer was washed with water thenbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo to giveIntermediate 153E (146.7 mg, 0.601 mmol, 97%) as a yellow oil: ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.52-7.47 (m, 2H), 7.44-7.31 (m, 4H), 6.55 (s,1H), 5.44 (s, 2H), 4.66 (s, 2H), 4.10 (br. s., 2H), 2.39 (d, J=0.4 Hz,3H); LC-MS: Method H, RT=0.93 min, MS (ESI) m/z: 245.2 (M+H)⁺.

Intermediate 153F: 3-amino-2-(benzyloxy)-6-methylisonicotinaldehyde

Intermediate 153E (146 mg, 0.598 mmol) was dissolved in CHCl₃ (3984 μL).Manganese dioxide (312 mg, 3.59 mmol) was added. After 2.5 hours, thereaction mixture was filtered through celite and concentrated in vacuoto give Intermediate 153F (125.7 mg, 0.519 mmol, 87%) as an orange oil:¹H NMR (400 MHz, CHLOROFORM-d) δ 9.81 (s, 1H), 7.43-7.37 (m, 2H),7.35-7.23 (m, 3H), 6.75 (s, 1H), 6.08 (br. s., 2H), 5.36 (s, 2H), 2.33(d, J=0.7 Hz, 3H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 243.3(M+H)⁺.

Intermediate 153G:8-(benzyloxy)-3-(methoxymethyl)-6-methyl-1,7-naphthyridine

Intermediate 153F (125 mg, 0.516 mmol), 3-methoxypropanal (50.0 mg,0.568 mmol), and sodium methoxide (0.5 M, 1135 μL, 0.568 mmol) weredissolved in MeOH (5159 μL) and heated to reflux for 3.5 hours. Thereaction mixture was diluted with saturated NH₄Cl and EtOAc. The layerswere separated and the organic layer was washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 24 g silica gel column, 19minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate153G (47 mg, 0.160 mmol, 30.9%) as a yellow oil: ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.85 (d, J=2.0 Hz, 1H), 7.96-7.91 (m, 1H), 7.65-7.59 (m,2H), 7.41-7.34 (m, 2H), 7.33-7.29 (m, 1H), 7.03 (d, J=0.7 Hz, 1H),7.04-7.00 (m, 1H), 5.74 (s, 2H), 4.66 (d, J=0.7 Hz, 2H), 3.49 (s, 3H),2.57 (d, J=0.7 Hz, 3H); LC-MS: Method H, RT=1.16 min, MS (ESI) m/z:295.3 (M+H)⁺.

Intermediate 153H: 3-(methoxymethyl)-6-methyl-1,7-naphthyridin-8-ol

Intermediate 153G (47 mg, 0.160 mmol) was dissolved in MeOH (1597 μL).Palladium on carbon (16.99 mg, 0.016 mmol) was added and the reactionmixture was sealed under a balloon of hydrogen for 30 minutes. Thereaction mixture was filtered through a micron filter and concentratedin vacuo to give Intermediate 153H (29.6 mg, 0.145 mmol, 91%) as ayellow solid: LC-MS: Method H, RT=0.71 min, MS (ESI) m/z: 205.2 (M+H)⁺.

Intermediate 153I: 8-chloro-3-(methoxymethyl)-6-methyl-1,7-naphthyridine

Intermediate 153H (29.6 mg, 0.145 mmol) was dissolved in POCl₃ (675 μL,7.25 mmol) and heated to 90° C. for 5 hours. The reaction mixture wasdiluted with EtOAc and quenched with water. The organic layer was washedwith saturated NaHCO₃, brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to give Intermediate 153I (24.3 mg, 0.109 mmol, 75%) as a brownsolid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.99 (d, J=2.0 Hz, 1H),8.09-8.04 (m, 1H), 7.44 (s, 1H), 4.72 (d, J=0.9 Hz, 2H), 3.53 (s, 3H),2.72 (s, 3H); LC-MS: Method H, RT=0.83 min, MS (ESI) m/z: 223.2 (M+H)⁺.

Intermediate 153J:6-methoxy-4-methyl-2-(tributylstannyl)benzo[d]thiazole

Intermediate I-3 (20 mg, 0.077 mmol) was dissolved in Et₂O (310 μL) andcooled to −78° C. BuLi (2.5 M, 34.1 μL, 0.085 mmol) was added. After 30minutes, tributylchlorostannane (21.02 μL, 0.077 mmol) was added. After45 minutes, the reaction mixture was warmed to ambient temperature andconcentrated in vacuo. The crude material was suspended in hexanes andfiltered through dry celite. The residue was concentrated in vacuo togive Intermediate 153J, which was used directly in the next reaction.

Example 153

Intermediate 153I (10 mg, 0.045 mmol), Intermediate 153J (30.5 mg, 0.065mmol), and potassium acetate (8.82 mg, 0.090 mmol) were dissolved indioxane (449 μL) and degassed by bubbling with argon for 15 minutes.Palladium tetrakistriphenylphosphine (2.59 mg, 2.245 μmol) was added andthe reaction mixture was sealed and heated to 120° C. in the microwavefor 2 hours. The reaction mixture was diluted with EtOAc, washed withwater, then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude material was diluted with DMF, filtered, and purified bypreparative HPLC (Method D, 20 to 60% B in 15 minutes) to give Example153 (6 mg, 0.016 mmol, 35.8%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.06 (d,J=2.2 Hz, 1H), 8.39-8.34 (m, 1H), 7.91 (s, 1H), 7.57 (d, J=2.5 Hz, 1H),7.07-6.99 (m, 1H), 4.75 (s, 2H), 3.88 (s, 3H), 3.44 (s, 3H), 2.78 (s,3H), 2.76 (s, 3H); LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 366.1(M+H)⁺; Analytical HPLC Method B: 98% purity.

Example 154(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol

Intermediate I-9 (12.77 mg, 0.043 mmol), Intermediate I-20D (14 mg,0.051 mmol), and potassium phosphate tribasic (18.07 mg, 0.085 mmol)were dissolved in DMF (426 μL) and degassed by bubbling with argon for15 minutes. Palladium tetrakistriphenylphosphine (4.92 mg, 4.26 μmol)was added and degassing continued for 5 minutes. The reaction mixturewas heated to 85° C. for 18 hours. The reaction mixture was diluted withDMF, filtered, and purified by preparative HPLC (Method D, 45 to 90% Bin 10 minutes) to give Example 154 (4.5 mg, 0.011 mmol, 26.5%): ¹H NMR(500 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.59 (s, 1H), 7.82 (s, 1H), 7.59 (d,J=2.2 Hz, 1H), 7.22 (d, J=1.7 Hz, 1H), 5.38 (t, J=5.8 Hz, 1H), 5.13 (d,J=5.5 Hz, 2H), 4.09 (s, 3H), 3.89 (s, 3H), 2.65 (s, 3H); LC-MS: MethodH, RT=1.26 min, MS (ESI) m/z: 368.2 (M+H)⁺; Analytical HPLC Method B:92% purity.

Example 155(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol

Intermediate I-2 (13.37 mg, 0.043 mmol), Intermediate I-20D (14 mg,0.051 mmol), and potassium phosphate tribasic (18.07 mg, 0.085 mmol)were dissolved in DMF (426 μL) and degassed by bubbling with argon for15 minutes. Palladium tetrakistriphenylphosphine (4.92 mg, 4.26 μmol)was added and degassing continued for 5 minutes. The reaction mixturewas heated to 85° C. for 18 hours. The reaction mixture was diluted withDMF, filtered, and purified by preparative HPLC (Method D, 30 to 70% Bin 12 minutes) to give Example 155 (3.9 mg, 0.01012 mmol, 23.8%): ¹H NMR(500 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.81 (s, 1H), 8.04 (s, 1H), 7.62 (d,J=2.2 Hz, 1H), 7.22 (d, J=1.4 Hz, 1H), 5.40 (t, J=5.6 Hz, 1H), 5.14 (d,J=5.5 Hz, 2H), 4.82 (s, 2H), 3.90 (s, 3H), 3.49 (s, 3H), 2.71 (s, 3H);LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 382.1 (M+H)⁺; AnalyticalHPLC Method B: 99% purity.

Example 1561-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol

Intermediate 156A: 1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)ethanol

Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) andcooled to −78° C. Methylmagnesium bromide (61.2 μL, 0.184 mmol) wasadded. After 1 hour, the reaction mixture was warmed to 0° C. andstirred for 18 hours. The reaction mixture was quenched with saturatedNH₄Cl and extracted with EtOAc. The organic layer was washed with water,then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 12 g silicagel column, 17 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 156A (26.8 mg, 0.093 mmol, 63.3%) as a clear oil: ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.17-7.11 (m, 1H), 7.08-7.04 (m, 1H),5.41-5.31 (m, 1H), 3.87 (s, 3H), 3.44-3.34 (m, 1H), 1.66-1.60 (m, 3H);LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 288/290 (M+H)⁺.

Example 156

Intermediate I-2 (12.18 mg, 0.039 mmol), Intermediate 156A (13.4 mg,0.047 mmol), and potassium phosphate tribasic (16.45 mg, 0.078 mmol)were dissolved in DMF (388 μL) and degassed by bubbling with argon for15 minutes. Palladium tetrakistriphenylphosphine (4.48 mg, 3.88 μmol)was added and degassing continued for 5 minutes. The reaction mixturewas heated to 85° C. for 18 hours. The reaction mixture was diluted withDMF, filtered, and purified by preparative HPLC (Method D, 30 to 70% Bin 20 minutes) to give Example 156 (5.1 mg, 0.012 mmol, 31.9%): ¹H NMR(500 MHz, DMSO-d₆) δ 9.11 (br. s., 1H), 8.80 (br. s., 1H), 8.05 (br. s.,1H), 7.61 (br. s., 1H), 7.25 (br. s., 1H), 5.68 (d, J=4.7 Hz, 1H), 4.83(br. s., 2H), 3.89 (br. s., 3H), 3.49 (br. s., 3H), 2.71 (br. s., 3H),1.57 (d, J=5.0 Hz, 3H); LC-MS: Method H, RT=1.13 min, MS (ESI) m/z:396.2 (M+H)⁺; Analytical HPLC Method B: 96% purity.

Example 1572-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)propan-2-ol

Intermediate 157A: 2-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)propan-2-ol

Intermediate I-20C (50 mg, 0.165 mmol) was dissolved in THF (331 μL) andcooled to −78° C. Methylmagnesium bromide (124 μL, 0.372 mmol) was addedand the reaction mixture warmed to 0° C. for 18 hours. The reactionmixture was quenched with saturated NH₄Cl and extracted with EtOAc. Theorganic layer was washed with water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 12 g silica gel column, 17 minute gradientfrom 0 to 100% EtOAc in hexanes) to give Intermediate 157A (13.6 mg,0.045 mmol, 27.2%) as a clear oil: LC-MS: Method H, RT=1.00 min, MS(ESI) m/z: 302/304 (M+H)⁺.

Example 157

Intermediate I-2 (11.78 mg, 0.038 mmol), Intermediate 157A (13.6 mg,0.045 mmol), and potassium phosphate tribasic (15.92 mg, 0.075 mmol)were dissolved in DMF (375 μL) and degassed by bubbling with argon for15 minutes. Palladium tetrakistriphenylphosphine (4.33 mg, 3.75 μmol)was added and degassing continued for 5 minutes. The reaction mixturewas heated to 85° C. for 18 hours. The reaction mixture was diluted withDMF, filtered, and purified by preparative HPLC (Method D, 40 to 80% Bin 15 minutes) to give Example 157 (8.1 mg, 0.020 mmol, 52.2%): ¹H NMR(500 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.73 (d, J=1.9 Hz, 1H), 8.07-8.02 (m,1H), 7.62 (d, J=2.5 Hz, 1H), 7.36 (d, J=2.8 Hz, 1H), 5.42 (s, 1H), 4.83(s, 2H), 3.89 (s, 3H), 3.49 (s, 3H), 2.71 (s, 3H), 1.84 (s, 6H); LC-MS:Method H, RT=1.12 min, MS (ESI) m/z: 410.2 (M+H)⁺; Analytical HPLCMethod B: 99% purity.

Example 158Cyclopropyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol

Intermediate 158A:(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(cyclopropyl)methanol

Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) andcooled to −78° C. Cyclopropylmagnesium bromide (367 μL, 0.184 mmol) wasadded and the reaction mixture was warmed to 0° C. for 18 hours. Thereaction mixture was quenched with saturated NH₄Cl and extracted withEtOAc. The organic layer was washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 12 g silica gel column, 17minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate158A (24.5 mg, 0.078 mmol, 53%) as a yellow oil, which was used directlyin the subsequent reaction.

Example 158

Intermediate I-2 (14.40 mg, 0.046 mmol), Intermediate 158A (12 mg, 0.038mmol), and potassium phosphate tribasic (16.21 mg, 0.076 mmol) weredissolved in DMF (382 μL) and degassed by bubbling with argon for 15minutes. Palladium tetrakistriphenylphosphine (4.41 mg, 3.82 μmol) wasadded and degassing continued for 5 minutes. The reaction mixture washeated to 85° C. for 18 hours. The reaction mixture was diluted withDMF, filtered, and purified by preparative HPLC (Method D, 35 to 75% Bin 15 minutes) to give Example 158 (9.2 mg, 0.022 mmol, 57.1%): ¹H NMR(500 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.78 (d, J=1.7 Hz, 1H), 8.05 (s, 1H),7.63 (d, J=2.5 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 5.35 (d, J=4.7 Hz, 1H),5.14 (dd, J=6.5, 5.1 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H),2.71 (s, 3H), 1.36-1.27 (m, 1H), 0.62 (dt, J=9.1, 4.5 Hz, 1H), 0.54 (td,J=9.1, 5.1 Hz, 1H), 0.49-0.42 (m, 1H), 0.42-0.34 (m, 1H); LC-MS: MethodH, RT=1.11 min, MS (ESI) m/z: 421.8 (M+H)⁺; Analytical HPLC Method B:100% purity.

Example 1591-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-N,N-dimethylmethanamine

Intermediate 159A: methyl 5-methoxy-2-nitrobenzoate

5-methoxy-2-nitrobenzoic acid (2 g, 10.14 mmol) was dissolved in MeOH(50.7 mL). SOCl₂ (2.96 mL, 40.6 mmol) was added and the reaction mixturewas heated to reflux for 20 hours. The reaction mixture was concentratedin vacuo. The crude material was dissolved in EtOAc and washed with 1 NNaOH, then water, then brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to give Intermediate 159A (1.7786 g, 8.42 mmol, 83%) as a brownoil: ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (d, J=9.0 Hz, 1H), 7.07-6.99(m, 2H), 3.94 (s, 3H), 3.92 (s, 3H); LC-MS: Method H, The compound didnot ionize.

Intermediate 159B: (5-methoxy-2-nitrophenyl)methanol

Intermediate 159A (1.676 g, 7.94 mmol) was dissolved in toluene (52.9mL) and THF (26.5 mL) and cooled to −78° C. DIBAL-H (17.46 mL, 17.46mmol) was added for 30 minutes. The reaction mixture was warmed toambient temperature for 2 hours. The reaction was quenched with 1 N HCland stirred for 18 hours. The reaction mixture was diluted with EtOAc,filtered through celite, washed with water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 80 g silica gel column, 29 minute gradientfrom 0 to 100% EtOAc in hexanes) to give Intermediate 159B (1.21 g, 6.61mmol, 83%) as a yellow solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (d,J=9.0 Hz, 1H), 7.22 (d, J=2.9 Hz, 1H), 6.90 (dd, J=9.0, 2.9 Hz, 1H),5.00 (d, J=6.4 Hz, 2H), 3.92 (s, 3H), 2.55 (t, J=6.6 Hz, 1H); LC-MS:Method H, The compound did not ionize.

Intermediate 159C: 5-methoxy-2-nitrobenzyl methanesulfonate

Intermediate 159B (0.2 g, 1.092 mmol) and TEA (0.457 mL, 3.28 mmol) weredissolved in DCM (21.84 mL). Methanesulfonic anhydride (0.228 g, 1.310mmol) was added for 45 minutes. The reaction mixture was diluted withDCM and washed with saturated NaHCO₃, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 159C. The material was usedcrude in the next step.

Intermediate 159D: 1-(5-methoxy-2-nitrophenyl)-N,N-dimethylmethanamine

Intermediate 159C (0.285 g, 1.091 mmol), DIEA (0.286 mL, 1.636 mmol),and dimethylamine (1.091 mL, 2.182 mmol) were dissolved in THF (10.91mL) for 18 hours. The reaction mixture was concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 40 g silicagel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 159D (66.4 mg, 0.316 mmol, 29%) as a yellow oil: ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.99 (d, J=9.0 Hz, 1H), 7.24 (d, J=2.9 Hz,1H), 6.83 (dd, J=9.0, 2.9 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 2H), 2.27 (s,6H); LC-MS: Method H, RT=0.54 min, MS (ESI) m/z: 211.2 (M+H)⁺.

Intermediate 159E: 2-((dimethylamino)methyl)-4-methoxyaniline, TFA

Intermediate 159D (66 mg, 0.314 mmol) was dissolved in MeOH (2147 μL)and THF (268 μL). Ammonium chloride (336 mg, 6.28 mmol) and zinc (205mg, 3.14 mmol) were added and the reaction mixture was heated to 40° C.for 4.5 hours. The reaction mixture was diluted with EtOAc and saturatedsodium carbonate and allowed to stir vigorously for 15 minutes. Themixture was filtered through a sintered glass funnel. The organic layerwas washed with water then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by preparativeHPLC (Method A, 20 to 100% B in 12 minutes) to give Intermediate 159E(34.3 mg, 0.117 mmol, 37.1%) as a brown oil: ¹H NMR (400 MHz, MeOH-d₄) δ6.99-6.94 (m, 2H), 6.93-6.89 (m, 1H), 4.30 (s, 2H), 3.77 (s, 3H), 2.87(s, 6H); LC-MS: Method H, RT=0.55 min, MS (ESI) m/z: 181.2 (M+H)⁺.

Intermediate 159F:4-((dimethylamino)methyl)-6-methoxybenzo[d]thiazol-2-amine

Intermediate 159E (34.3 mg, 0.117 mmol) was dissolved in MeCN (583 μL).Ammonium thiocyanate (13.31 mg, 0.175 mmol) was added, followed bybenzyltrimethylammonium tribromide (45.5 mg, 0.117 mmol) for 18 hours.The reaction mixture was diluted with EtOAc, washed with saturatedNaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentrated in vacuoto give Intermediate 159F (10.3 mg, 0.043 mmol, 37.2%) as a yellow oil:LC-MS: Method H, RT=1.01 min, MS (ESI) m/z: 238.1 (M+H)⁺.

Intermediate 159G:1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-N,N-dimethylmethanamine

Copper(II) bromide (16.00 mg, 0.072 mmol) and t-butyl nitrite (8.52 μL,0.072 mmol) were dissolved in MeCN (1694) and allowed to stir 10minutes. Intermediate 159F (10 mg, 0.042 mmol) was dissolved in MeCN(2534) and the copper solution was added at and the reaction mixture wasstirred for 75 minutes. The reaction mixture was diluted with EtOAc,washed with 1 N HCl, saturated NaHCO₃, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate 159G (9.8 mg,0.033 mmol, 77%), which was used as-is for the subsequent step: LC-MS:Method H, RT=1.017 min, MS (ESI) m/z: 301/303 (M+H)⁺.

Example 159

Intermediate I-2 (12.27 mg, 0.039 mmol), Intermediate 159G (9.8 mg,0.033 mmol), and potassium phosphate tribasic (13.81 mg, 0.065 mmol)were dissolved in DMF (325 μL) and degassed by bubbling with argon for15 minutes. Palladium tetrakistriphenylphosphine (3.76 mg, 3.25 μmol)was added and degassing continued for 5 minutes. The reaction mixturewas heated to 85° C. for 18 hours. The reaction mixture was diluted withDMF, filtered, and purified by preparative HPLC (Method D, 20 to 60% Bin 20 minutes) then repurified by preparative HPLC (Method D, 20 to 60%B in 15 minutes) to give Example 159 (2.8 mg, 0.00651 mmol, 20%): ¹H NMR(500 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.90 (d, J=1.7 Hz, 1H), 8.08 (s, 1H),7.82 (d, J=1.9 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 4.82 (s, 2H), 4.59 (br.s., 2H), 3.91 (s, 3H), 3.48 (s, 3H), 2.72 (s, 6H) (1 methyl group buriedunder the water peak); LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 408.8(M+H)⁺; Analytical HPLC Method B: 95% purity.

Example 160Cyclopropyl(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol

Intermediate I-9 (13.76 mg, 0.046 mmol), Intermediate 158A (12 mg, 0.038mmol), and potassium phosphate tribasic (16.21 mg, 0.076 mmol) weredissolved in DMF (382 μL) and degassed by bubbling with argon for 15minutes. Palladium tetrakistriphenylphosphine (4.41 mg, 3.82 μmol) wasadded and degassing continued for 5 minutes. The reaction mixture washeated to 85° C. for 18 hours. The reaction mixture was diluted withDMF, filtered, and purified by preparative HPLC (Method D, 45 to 85% Bin 15 minutes) to give Example 160 (4.2 mg, 0.0103 mmol, 27%): ¹H NMR(500 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.55 (d, J=1.7 Hz, 1H), 7.83 (s, 1H),7.60 (d, J=2.5 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 5.35 (d, J=5.0 Hz, 1H),5.13 (dd, J=6.5, 5.1 Hz, 1H), 4.09 (s, 3H), 3.89 (s, 3H), 2.65 (s, 3H),1.34-1.27 (m, 1H), 0.61 (dt, J=9.0, 4.4 Hz, 1H), 0.57-0.50 (m, 1H),0.49-0.42 (m, 1H), 0.42-0.34 (m, 1H); LC-MS: Method H, RT=1.21 min, MS(ESI) m/z: 407.8 (M+H)⁺; Analytical HPLC Method B: 98% purity.

Example 161(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(phenyl)methanol

Intermediate 161A:(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(phenyl)methanol

Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) andcooled to −78° C. Phenylmagnesium bromide (61.2 μL, 0.184 mmol) wasadded and the reaction mixture was warmed to 0° C. for 18 hours. Thereaction mixture was quenched with saturated NH₄Cl and extracted withEtOAc. The organic layer was washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 12 g silica gel column, 17minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate161A (33.6 mg, 0.096 mmol, 65.3%) as a white solid: LC-MS: Method H,RT=1.01 min, MS (ESI) m/z: 350/352 (M+H)⁺.

Example 161

Intermediate I-2 (14.80 mg, 0.047 mmol), Intermediate 161A (16.5 mg,0.047 mmol), and potassium phosphate tribasic (20.00 mg, 0.094 mmol)were dissolved in DMF (471 μL) and degassed by bubbling with argon for15 minutes. Palladium tetrakistriphenylphosphine (5.44 mg, 4.71 μmol)was added and degassing continued for 5 minutes. The reaction mixturewas heated to 85° C. for 18 hours. The reaction mixture was diluted withDMF, filtered, and purified by preparative HPLC (Method D, 40 to 75% Bin 15 minutes) to give Example 161 (11 mg, 0.024 mmol, 50%): ¹H NMR (500MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.83 (d, J=1.7 Hz, 1H), 8.06 (d, J=0.6 Hz,1H), 7.65-7.57 (m, 3H), 7.35-7.27 (m, 3H), 7.23-7.16 (m, 1H), 6.72 (d,J=4.1 Hz, 1H), 6.10 (d, J=4.4 Hz, 1H), 4.82 (s, 2H), 3.87 (s, 3H), 3.48(s, 3H), 2.74 (s, 3H); LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 457.8(M+H)⁺; Analytical HPLC Method B: 98% purity.

Example 1626-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxylicacid

Intermediate 162A: 5-methoxy-2-nitrobenzoyl chloride

5-Methoxy-2-nitrobenzoic acid (1 g, 5.07 mmol) was dissolved in DCM(50.7 mL). Oxalyl chloride (0.958 mL, 11.16 mmol) then DMF (0.039 mL,0.507 mmol) was added at ambient temperature and the reaction mixturewas stirred for 2.5 hours. The reaction mixture was concentrated invacuo and stored on HIVAC to give Intermediate 162A, which was useddirectly in the subsequent reaction.

Intermediate 162B: tert-butyl 5-methoxy-2-nitrobenzoate

Intermediate 162A (1.094 g, 5.07 mmol) was dissolved in THF (50.7 mL).Potassium tert-butoxide (0.854 g, 7.61 mmol) was added and the reactionmixture was stirred for 18 hours. The reaction mixture was diluted withEtOAc and washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 162B (910 mg, 3.59 mmol,70.8%) as a brown oil: ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.98 (d, J=9.0Hz, 1H), 7.03 (d, J=2.9 Hz, 1H), 6.98 (dd, J=9.0, 2.6 Hz, 1H), 3.91 (s,3H), 1.58 (s, 9H); LC-MS: Method H, the compound did not ionize.

Intermediate 162C: tert-butyl 2-amino-5-methoxybenzoate

Intermediate 162B (0.910 g, 3.59 mmol) was dissolved in EtOH (5.13 mL).Palladium on carbon (0.076 g, 0.072 mmol) then ammonium formate (1.133g, 17.97 mmol) was added and the reaction mixture was heated to refluxfor 1.5 hours. The reaction mixture was filtered through celite andconcentrated in vacuo to give Intermediate 162C (795 mg, 3.56 mmol, 99%)as a brown oil: ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.33 (d, J=2.9 Hz, 1H),6.92 (dd, J=8.8, 3.1 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 5.36 (br. s., 2H),3.76-3.74 (m, 3H), 1.59 (s, 9H); LC-MS: Method H, The compound did notionize.

Intermediate 162D: tert-butyl2-amino-6-methoxybenzo[d]thiazole-4-carboxylate

Intermediate 162C (0.795 g, 3.56 mmol) was dissolved in MeCN (17.80 mL).Ammonium thiocyanate (0.407 g, 5.34 mmol) was added, followed bybenzyltrimethylammonium tribromide (1.389 g, 3.56 mmol) for 18 hours.The reaction mixture was diluted with EtOAc, washed with saturatedNaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude material was purified by column chromatography (ISCO, 80 gsilica gel column, 29 minute gradient from 0 to 100% EtOAc in hexanes)to give Intermediate 162D (685.8 mg, 2.446 mmol, 68.7%) as a yellowsolid: ¹H NMR (400 MHz, chloroform-d) δ 7.46 (d, J=2.6 Hz, 1H), 7.29 (d,J=2.6 Hz, 1H), 5.71 (br. s., 2H), 3.85 (s, 3H), 1.63 (s, 9H); LC-MS:Method H, RT=1.32 min, MS (ESI) m/z: 282.1 (M+H)⁺.

Intermediate 162E: tert-butyl2-bromo-6-methoxybenzo[d]thiazole-4-carboxylate

Copper(II) bromide (0.928 g, 4.15 mmol) and t-butyl nitrite (0.494 mL,4.15 mmol) were dissolved in MeCN (9.77 mL) and allowed to stir 10minutes. Intermediate 162D (0.685 g, 2.443 mmol) was dissolved in MeCN(14.66 mL) and the copper solution was added for 2.5 hours. The reactionmixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO₃,then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 80 g silicagel column, 29 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 162E (323.8 mg, 0.941 mmol, 38.5%) as a white solid: ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.59 (d, J=2.6 Hz, 1H), 7.40 (d, J=2.6 Hz,1H), 3.90 (s, 3H), 1.65 (s, 9H); LC-MS: The compound did not ionize.

Intermediate 162F: tert-butyl6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole-4-carboxylate

Intermediate I-2 (22.82 mg, 0.073 mmol), Intermediate 162E (25 mg, 0.073mmol), and potassium phosphate tribasic (30.8 mg, 0.145 mmol) weredissolved in DMF (726 μL) and degassed by bubbling with argon for 15minutes. Palladium tetrakistriphenylphosphine (8.39 mg, 7.26 μmol) wasadded and degassing continued for 5 minutes. The reaction mixture washeated to 85° C. for 18 hours. The reaction mixture was diluted withwater and extracted thrice with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude material was purified by column chromatography (ISCO, 12 gsilica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes)to give Intermediate 162F (14.7 mg, 0.033 mmol, 44.8%) as an orangesolid: LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 452.2 (M+H)⁺.

Example 162

Intermediate 162F (14.7 mg, 0.033 mmol) was dissolved in DCM (1085 μL)and cooled to 0° C. 2,6-Lutidine (11.38 μL, 0.098 mmol) and TMS-OTf(17.65 μL, 0.098 mmol) were added and the reaction mixture was warmed toambient temperature for 45 minutes. The reaction mixture was dilutedwith water and extracted with DCM. The organic layer was washed withbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crudematerial was dissolved in DMF, filtered, and purified by preparativeHPLC (Method D, 20 to 60% B in 12 minutes) to give Example 162 (5.5 mg,0.014 mmol, 42.3%): LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 396.1(M+H)⁺; Analytical HPLC Method B: 99% purity.

Example 163(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(phenyl)methanol

Example 161 (8 mg, 0.017 mmol) was purified by SFC chromatography(Berger Multigram II SFC, Chiralpak OJ-H, 21×250 mm, 5 micron, 25%MeOH/75% CO₂, 45 mL/min flow rate) to give Enantiomer 1 (1.54 mg, 0.0032mmol, 19%) and Example 163 (Enantiomer 2, 3.4 mg, 0.00706 mmol, 40.4%)as a yellow solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.08 (s, 1H), 8.75(d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J=7.5 Hz, 2H), 7.39-7.33 (m,2H), 7.32 (d, J=2.4 Hz, 1H), 7.28 (d, J=7.5 Hz, 1H), 6.86 (d, J=2.0 Hz,1H), 6.40 (d, J=5.7 Hz, 1H), 5.78 (d, J=6.2 Hz, 1H), 4.84 (s, 2H), 3.86(s, 3H), 3.58 (s, 3H), 2.70 (s, 3H); LC-MS: Method H, RT=1.11 min, MS(ESI) m/z: 458.3 (M+H)⁺; 95% purity.

Example 1641-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 164A:1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate I-20 (100 mg, 0.367 mmol) was dissolved in THF (3675 μL)and cooled to −78° C. tert-Butylmagnesium chloride (1 M, 735 μl, 0.735mmol) was added and warmed to 0° C. for 2 hours. The reaction wasquenched with saturated NH₄Cl and extracted with EtOAc. The organiclayer was washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 24 g silica gel column, 17 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate 164A (74.2 mg, 0.225mmol, 61.1%) as a yellow solid: LC-MS: Method H, RT=1.07 min, MS (ESI)m/z: 330/332 (M+H)⁺.

Intermediate 164B:1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate I-2 (58.8 mg, 0.187 mmol) and Intermediate 164A (74.2 mg,0.225 mmol) were dissolved in DMF (1872 μL). PdCl₂(dppf)-CH₂Cl₂ (9.17mg, 0.011 mmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 112 μL, 0.225mmol) was added and the reaction mixture was degassed for 5 minutes,then sealed and heated to 100° C. in the microwave for 30 minutes. Thereaction mixture was diluted with EtOAc, washed with water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude materialwas purified by column chromatography (ISCO, 24 g silica gel column, 19minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate164B (45 mg, 0.103 mmol, 54.9%) as a yellow solid: ¹H NMR (500 MHz,DMSO-d₆) δ 9.11 (s, 1H), 8.77 (d, J=1.9 Hz, 1H), 8.05 (s, 1H), 7.65 (d,J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.45 (d, J=4.7 Hz, 1H), 5.34 (d,J=4.7 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.72 (s, 3H),0.97 (s, 9H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 438.2 (M+H)⁺.

Example 164

Intermediate 164B (62 mg, 0.017 mmol) was purified by SFC chromatography(Berger Multigram II SFC, Chiralpak OJ-H, 21×250 mm, 5 micron, 25%MeOH/75% CO₂, 45 mL/min flow rate) to give Enantiomer 1 (15.2 mg, 0.034mmol, 24.3%) and Example 164 (Enantiomer 2, 18.3 mg, 0.040 mmol, 28%) asa yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.77 (d, J=1.9Hz, 1H), 8.05 (s, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H),5.45 (d, J=4.7 Hz, 1H), 5.34 (d, J=4.7 Hz, 1H), 4.83 (s, 2H), 3.89 (s,3H), 3.48 (s, 3H), 2.72 (s, 3H), 0.97 (s, 9H); LC-MS: Method H, RT=1.19min, MS (ESI) m/z: 438.2 (M+H)⁺; 95% purity.

Example 165Cyclohexyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-methanol

Intermediate 165A:(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(cyclohexyl)methanol

Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF (735 μL) andcooled to −78° C. Cyclohexylmagnesium bromide (1 M, 147 μL, 0.147 mmol)was added and the reaction mixture was warmed to 0° C. for 5 hours. Thereaction was quenched with saturated NH₄Cl and extracted with EtOAc. Theorganic layer was washed with water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 12 g silica gel column, 17 minute gradientfrom 0 to 100% EtOAc in hexanes) to give Intermediate 165A (5.3 mg,0.015 mmol, 20.2%) as a clear oil: LC-MS: Method H, RT=1.13 min, MS(ESI) m/z: 356/358 (M+H)⁺.

Example 165

Intermediate I-2 (5.61 mg, 0.018 mmol) and Intermediate 165A (5.3 mg,0.015 mmol) were dissolved in DMF (149 μL). PdCl₂(dppf)-CH₂Cl₂ (0.729mg, 0.893 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 8.93 μL,0.018 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 70 to 100% B in 20 minutes) togive Example 165 (2.9 mg, 0.00626 mmol, 42.1%): ¹H NMR (500 MHz,DMSO-d₆) δ 9.10 (s, 1H), 8.75 (d, J=1.7 Hz, 1H), 8.04 (s, 1H), 7.61 (d,J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.37 (t, J=5.6 Hz, 1H), 5.22 (d,J=5.2 Hz, 1H), 4.82 (s, 2H), 3.88 (s, 3H), 3.48 (s, 3H), 2.71 (s, 3H),1.89 (br. s., 1H), 1.81 (d, J=5.8 Hz, 1H), 1.70 (br. s., 1H), 1.66 (d,J=3.6 Hz, 1H), 1.59 (br. s., 1H), 1.44 (d, J=9.4 Hz, 1H), 1.21-1.09 (m,5H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 464.3 (M+H)⁺;Analytical HPLC Method B: 100% purity.

Example 166Cyclobutyl(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol

Intermediate 166A:(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(cyclobutyl)methanol

Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF (735 μL) andcooled to −78° C. Cyclobutylmagnesium bromide (0.25 M, 588 μL, 0.147mmol) was added and the reaction mixture was warmed to 0° C. for 18hours. The reaction was quenched with saturated NH₄Cl and extracted withEtOAc. The organic layer was washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 12 g silica gel column, 17minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate166A (4 mg, 0.012 mmol, 16.6%): LC-MS: Method H, RT=0.82 min, MS (ESI)m/z: 328/330 (M+H)⁺.

Example 166

Intermediate I-2 (4.59 mg, 0.015 mmol) and Intermediate 166A (4 mg,0.012 mmol) were dissolved in DMF (122 μL). PdCl₂(dppf)-CH₂Cl₂ (0.597mg, 0.731 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 7.31 μL,0.015 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 50 to 100% B in 23 minutes) togive Example 166 (2.7 mg, 0.00595 mmol, 48.8%): ¹H NMR (500 MHz,CHLOROFORM-d) δ 9.01 (s, 1H), 8.67 (d, J=1.4 Hz, 1H), 7.89 (s, 1H), 7.25(d, J=2.2 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 4.95 (d, J=8.0 Hz, 1H), 4.77(s, 2H), 3.87-3.82 (m, 3H), 3.51 (s, 3H), 2.92-2.84 (m, 1H), 2.65 (s,3H), 2.18-2.06 (m, 2H), 1.91 (br. s., 1H), 1.86-1.75 (m, 3H); LC-MS:Method H, RT=1.15 min, MS (ESI) m/z: 436.2 (M+H)⁺; Analytical HPLCMethod B: 96% purity.

Example 167(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(pyridin-2-yl)methanol

Intermediate 167A:(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(pyridin-2-yl)methanol

Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF (735 μL) andcooled to −78° C. Pyridin-2-ylmagnesium bromide (0.25 M, 588 μL, 0.147mmol) was added and the reaction mixture was warmed to 0° C. for 18hours. The reaction was quenched with saturated NH₄Cl and extracted withEtOAc. The organic layer was washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 12 g silica gel column, 17minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate167A (9.1 mg, 0.026 mmol, 35.3%) as a yellow oil: LC-MS: Method H,RT=0.66 min, MS (ESI) m/z: 351/353 (M+H)⁺.

Example 167

Intermediate I-2 (9.77 mg, 0.031 mmol) and Intermediate 167A (9.1 mg,0.026 mmol) were dissolved in DMF (259 μL). PdCl₂(dppf)-CH₂Cl₂ (1.270mg, 1.555 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 15.55 μL,0.031 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 40 to 80% B in 20 minutes) togive Example 167 (2.7 mg, 0.00548 mmol, 21.1%): ¹H NMR (500 MHz,DMSO-d₆) δ 9.10 (s, 1H), 8.72 (d, J=1.4 Hz, 1H), 8.48 (d, J=4.4 Hz, 1H),8.04 (s, 1H), 7.90-7.80 (m, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.65 (d, J=2.5Hz, 1H), 7.31-7.22 (m, 1H), 7.14 (d, J=2.2 Hz, 1H), 6.72 (s, 1H), 6.22(br. s., 1H), 4.82 (s, 2H), 3.86 (s, 3H), 3.48 (s, 3H), 2.71 (s, 3H);LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 459.2 (M+H)⁺; AnalyticalHPLC Method B: 93% purity.

Example 168(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(pyridin-3-yl)methanol

Intermediate 168A:(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(pyridin-3-yl)methanol

Intermediate I-20 (20 mg, 0.073 mmol) was dissolved in THF (735 μL) andcooled to −78° C. Pyridin-3-ylmagnesium bromide (0.25 M, 588 μL, 0.147mmol) was added and the reaction mixture was warmed to 0° C. for 18hours. The reaction was quenched with saturated NH₄Cl and extracted withEtOAc. The organic layer was washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 12 g silica gel column, 17minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate168A (14.6 mg, 0.042 mmol, 56.6%) as a white solid: LC-MS: Method H,RT=0.65 min, MS (ESI) m/z: 351/353 (M+H)⁺.

Example 168

Intermediate I-2 (15.67 mg, 0.050 mmol) and Intermediate 168A (14.6 mg,0.042 mmol) were dissolved in DMF (416 μL). PdCl₂(dppf)-CH₂Cl₂ (2.037mg, 2.494 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 24.94 μL,0.050 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 35 to 75% B in 20 minutes) togive Example 168 (10 mg, 0.022 mmol, 51.9%): ¹H NMR (500 MHz, DMSO-d₆) δ9.09 (s, 1H), 8.86 (s, 1H), 8.80 (s, 1H), 8.41 (d, J=4.4 Hz, 1H), 8.04(s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.37 (d, J=2.5Hz, 1H), 7.34 (dd, J=8.0, 4.7 Hz, 1H), 6.73 (d, J=4.1 Hz, 1H), 6.29 (d,J=4.4 Hz, 1H), 4.82 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.73 (s, 3H);LC-MS: Method H, RT=0.79 min, MS (ESI) m/z: 459.2 (M+H)⁺; AnalyticalHPLC Method B: 99% purity.

Example 1691-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-1-d₁

Intermediate 169A: (2-bromo-6-methoxybenzo[d]thiazol-4-yl)methanol-d₂

Intermediate I-20C (370 mg, 1.225 mmol) was dissolved in toluene (8164μL) and THF (4082 μL) and cooled to −78° C. DIBAL-D (3849 μL, 2.69 mmol)was added and the reaction mixture was stirred for 30 minutes. Thereaction mixture was warmed to ambient temperature. After 1.5 hours, thereaction was quenched with 1 N HCl, stirred for 1 hour, and extractedwith EtOAc. The organic layer was washed with saturated NaHCO₃, thenbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crudematerial was purified by column chromatography (ISCO, 40 g silica gelcolumn, 19 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 169A (76.5 mg, 0.277 mmol, 22.5%) as a white solid: ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.17 (dd, J=7.7, 2.4 Hz, 1H), 7.05 (dd, 2.5Hz, 1H), 3.87 (s, 3H), 2.95 (d, J=15.0 Hz, 1H); LC-MS: Method H, RT=0.83min, MS (ESI) m/z: 276/278 (M+H)⁺.

Intermediate 169B: 2-bromo-6-methoxybenzo[d]thiazole-4-carbaldehyde-d₁

Intermediate 169A (76 mg, 0.275 mmol) was dissolved in CHCl₃ (1835 μL).Manganese dioxide (144 mg, 1.651 mmol) was added and the reactionmixture was heated to 40° C. for 18 hours. More manganese dioxide (144mg, 1.651 mmol) was added and heating continued for 36 hours. Thereaction mixture was filtered through celite and concentrated in vacuo.The crude material was purified by column chromatography (ISCO, 24 gsilica gel column, 17 minute gradient from 0 to 100% EtOAc in hexanes)to give Intermediate 169B (35.7 mg, 0.131 mmol, 47.5%) as a white solid:¹H NMR (400 MHz, CHLOROFORM-d) δ 7.62 (dd, J=5.1, 2.6 Hz, 1H), 7.54 (dd,J=8.1, 2.6 Hz, 1H), 3.93 (s, 3H); LC-MS: Method H, RT=0.95 min, MS (ESI)m/z: 275/277 (M+H)⁺.

Intermediate 169C:1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-1-d₁

Intermediate 169B (35 mg, 0.128 mmol) was dissolved in THF (1281 μL) andcooled to −78° C. tert-Butylmagnesium chloride (384 μL, 0.384 mmol) wasadded and the reaction mixture was warmed to 0° C. for 18 hours. Thereaction was quenched with saturated NH₄Cl and extracted with EtOAc. Theorganic layer was washed with water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 12 g silica gel column, 17 minute gradientfrom 0 to 100% EtOAc in hexanes) to give Intermediate 169C (27.1 mg,0.082 mmol, 63.8%) as a white solid: LC-MS: Method H, RT=1.06 min, MS(ESI) m/z: 331/333 (M+H)⁺.

Intermediate 169D:1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-1-d₁

Intermediate I-2 (30.8 mg, 0.098 mmol) and Intermediate 169C (27.1 mg,0.082 mmol) were dissolved in DMF (818 μL). PdCl₂(dppf)-CH₂Cl₂ (4.01 mg,4.91 μmol) was added and the reaction mixture was degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 49.1 μL, 0.098 mmol)was added and the reaction mixture was degassed for 5 minutes, thensealed and heated to 100° C. in the microwave for 30 minutes. Thereaction mixture was diluted with EtOAc, washed with water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude materialwas purified by column chromatography (ISCO, 12 g silica gel column, 19minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate169D (17.3 mg, 0.039 mmol, 48.2%) as a yellow solid: LC-MS: Method H,RT=1.18 min, MS (ESI) m/z: 439.3 (M+H)⁺.

Example 169

Intermediate 169D (17.3 mg, 0.039 mmol) was purified by SFCchromatography (Berger Multigram II SFC, Chiralpak OJ-H, 21×250 mm, 5micron, 25% MeOH/75% CO₂, 45 mL/min flow rate) to give Enantiomer 1 (6.5mg, 0.014 mmol, 35.7%) and Example 169 (Enantiomer 2, 6.5 mg, 0.014mmol, 35.7%) as a yellow solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.08(s, 1H), 8.69 (d, J=1.8 Hz, 1H), 7.96 (s, 1H), 7.34 (d, J=2.4 Hz, 1H),6.93 (d, J=2.4 Hz, 1H), 5.71 (s, 1H), 4.85 (s, 2H), 3.92 (s, 3H), 3.58(s, 3H), 2.72 (s, 3H), 1.05 (s, 9H); LC-MS: Method H, RT=1.18 min, MS(ESI) m/z: 439.3 (M+H)⁺; 95% purity.

Example 1701-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-d₅

Intermediate 170A:1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol-d₅

Intermediate I-25 (39.6 mg, 0.124 mmol) and Intermediate 164A (41 mg,0.124 mmol) were dissolved in DMF (1242 μL). PdCl₂(dppf)-CH₂Cl₂ (6.08mg, 7.45 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 74.5 μL,0.149 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. The reaction mixture was diluted with EtOAc, washed with water,then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 12 g silicagel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 170A (17.8 mg, 0.040 mmol, 32.4%) as a yellow solid: LC-MS:Method H, RT=1.18 min, MS (ESI) m/z: 443.3 (M+H)⁺.

Example 170

Intermediate 170A (19.8 mg, 0.045 mmol) was purified by SFCchromatography (Berger Multigram II SFC, Chiralpak OJ-H, 21×250 mm, 5micron, 25% MeOH/75% CO₂, 45 mL/min flow rate) to give Enantiomer 1 (7.7mg, 0.017 mmol, 36.9%) and Example 170 (Enantiomer 2, 7.8 mg, 0.017mmol, 37.4%) as a yellow solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.08(s, 1H), 8.69 (d, J=1.8 Hz, 1H), 7.96 (s, 1H), 7.34 (d, J=2.4 Hz, 1H),6.93 (d, J=2.4 Hz, 1H), 5.74 (br. s., 1H), 4.77 (br. s., 1H), 3.92 (s,3H), 2.72 (s, 3H), 1.05 (s, 9H); LC-MS: Method H, RT=1.18 min, MS (ESI)m/z: 443.3 (M+H)⁺; 95% purity.

Example 1712,2,2-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol

Intermediate 171A: 2-chloro-6-methoxybenzo[d]thiazole-4-carbaldehyde

Intermediate I-20 (250 mg, 0.919 mmol) was dissolved in THF (8352 μL)and concentrated HCl (835 μL) for 2.5 hours. The reaction mixture wasdiluted with EtOAc, washed with water, saturated NaHCO₃, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate171A (207 mg, 0.909 mmol, 99%) as an off-white solid: ¹H NMR (400 MHz,CHLOROFORM-d) δ 10.85 (s, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.53 (d, J=2.6Hz, 1H), 3.93 (s, 3H); LC-MS: Method H, RT=1.02 min, MS (ESI) m/z: 242.1(M+Na)⁺.

Intermediate 171B:1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-2,2,2-trifluoroethanol

Intermediate 171A (207 mg, 0.909 mmol) was dissolved in THF (18.2 mL).(Trifluoromethyl)trimethylsilane (161 μL, 1.091 mmol) then TBAF (1091μL, 1.091 mmol) were added and the reaction mixture was stirred for 18hours. The reaction mixture was diluted with EtOAc and washed withwater, saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate 171B (70.8 mg, 0.238mmol, 26.2%) as a white solid: LC-MS: Method H, RT=0.98 min, MS (ESI)m/z: 298.1 (M+H)⁺.

Example 171

Intermediate I-2 (30.0 mg, 0.096 mmol) and Intermediate 171B (23.7 mg,0.080 mmol) were dissolved in DMF (796 μL). PdCl₂(dppf)-CH₂Cl₂ (3.90 mg,4.78 μmol) was added and the reaction mixture was degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 47.8 μL, 0.096 mmol)was added and the reaction mixture was degassed for 5 minutes, thensealed and heated to 100° C. in the microwave for 30 minutes. Thereaction mixture was diluted with DMF, filtered, and purified bypreparative HPLC (Method D, 45 to 95% B in 20 minutes) to give Example171 (9.8 mg, 0.021 mmol, 26.6%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.12 (s,1H), 8.83 (br. s., 1H), 8.07 (br. s., 1H), 7.84 (br. s., 1H), 7.33 (br.s., 1H), 7.07 (d, J=5.8 Hz, 1H), 6.22 (br. s., 1H), 4.83 (s, 2H), 3.92(s, 3H), 3.49 (s, 3H), 2.72 (s, 3H); LC-MS: Method H, RT=1.08 min, MS(ESI) m/z: 450.2 (M+H)⁺; Analytical HPLC Method B: 97% purity.

Example 172(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(pyridin-4-yl)methanol

Intermediate 172A:(2-amino-6-methoxybenzo[d]thiazol-4-yl)(pyridin-4-yl)methanol

Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1930 μL).Sodium hydride (8.49 mg, 0.212 mmol) was added and the reaction mixturewas stirred for 10 minutes. The reaction mixture was cooled to −78° C.and BuLi (2.3 M, 101 μL, 0.232 mmol) was added, and the reaction mixturewas stirred for 1 hour. Isonicotinaldehyde (41.3 mg, 0.386 mmol) wasadded and the reaction mixture was allowed to warm to ambienttemperature. After 1 hour, the reaction mixture was diluted with EtOAcand washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 172A, which was used directlyin the subsequent reaction: LC-MS: Method H, RT=0.47 min, MS (ESI) m/z:288.2 (M+H)⁺.

Intermediate 172B:(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(pyridin-4-yl)methanol

Copper(II) chloride (36.0 mg, 0.268 mmol) and t-butyl nitrite (34.1 μL,0.287 mmol) were dissolved in MeCN (766 μL) and allowed to stir 10minutes. Intermediate 172A (55 mg, 0.191 mmol) was dissolved in MeCN(1148 μL) and the copper solution was added and the reaction mixture washeated to 60° C. for 2 hours. The reaction mixture was diluted withEtOAc, washed with saturated NaHCO₃, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The reaction mixture was purifiedby column chromatography (ISCO, 12 g silica gel column, 17 minutegradient from 0 to 20% MeOH in DCM) to give Intermediate 172B (11.5 mg,0.037 mmol, 19.6%) as a yellow solid: LC-MS: Method H, RT=0.63 min, MS(ESI) m/z: 307.1 (M+H)⁺.

Example 172

Intermediate I-2 (14.13 mg, 0.045 mmol) and Intermediate 172B (11.5 mg,0.037 mmol) were dissolved in DMF (375 μL). PdCl₂(dppf)-CH₂Cl₂ (1.837mg, 2.249 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 22.49 μL,0.045 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 35 to 75% B in 20 minutes) togive Example 172 (6 mg, 0.013 mmol, 34.9%): ¹H NMR (500 MHz, DMSO-d₆) δ9.10 (s, 1H), 8.83 (s, 1H), 8.57 (br. s., 2H), 8.06 (s, 1H), 7.70 (br.s., 2H), 7.67 (d, J=2.1 Hz, 1H), 7.26 (s, 2H), 6.75 (s, 1H), 4.83 (s,2H), 3.88 (s, 3H), 2.74 (s, 3H); LC-MS: Method H, RT=0.78 min, MS (ESI)m/z: 459.3 (M+H)⁺; Analytical HPLC Method B: 100% purity.

Example 1733,3,3-trifluoro-1-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)propan-1-ol

Intermediate 173A:1-(2-amino-6-methoxybenzo[d]thiazol-4-yl)-3,3,3-trifluoropropan-1-ol

Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1930 μL).Sodium hydride (8.49 mg, 0.212 mmol) was added and the reaction mixturewas stirred for 15 minutes. The reaction mixture was cooled to −78° C.and BuLi (2.3 M, 101 μL, 0.232 mmol) was added and the reaction mixturewas stirred for 30 minutes. 3,3,3-Trifluoropropanal (43.2 mg, 0.386mmol) was added and the reaction mixture was allowed to warm to ambienttemperature and stir for 1 hour. The reaction mixture was diluted withEtOAc and washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 173A, which was used directlyin the subsequent step: LC-MS: Method H, RT=0.65 min, MS (ESI) m/z:293.2 (M+H)⁺.

Intermediate 173B:1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-3,3,3-trifluoropropan-1-ol

Copper(II) chloride (36.3 mg, 0.270 mmol) and t-butyl nitrite (34.4 μL,0.289 mmol) were dissolved in MeCN (772 μL) and allowed to stir 10minutes. Intermediate 173A (56.4 mg, 0.193 mmol) was dissolved in MeCN(1158 μL) and the copper solution was added and the reaction mixture washeated to 60° C. After 3 hours, the reaction mixture was diluted withEtOAc, washed with 1 N HCl, saturated NaHCO₃, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 12 g silica gel column, 17minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate173B (9.4 mg, 0.030 mmol, 15.6%) as a yellow oil: LC-MS: Method H,RT=0.98 min, MS (ESI) m/z: 312.1 (M+H)⁺.

Example 173

Intermediate I-2 (11.37 mg, 0.036 mmol) and Intermediate 173B (9.4 mg,0.030 mmol) were dissolved in DMF (302 μL). PdCl₂(dppf)-CH₂Cl₂ (1.478mg, 1.809 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 18.09 μL,0.036 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. More PdCl₂(dppf)-CH₂Cl₂ (1.478 mg, 1.809 μmol) was added andthe reaction mixture was heated to 100° C. for 30 minutes in themicrowave. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 45 to 85% B in 25 minutes) togive Example 173 (2.5 mg, 0.00523 mmol, 17.4%): ¹H NMR (500 MHz,DMSO-d₆) δ 9.10 (s, 1H), 8.75 (s, 1H), 8.05 (s, 1H), 7.68 (d, J=2.1 Hz,1H), 7.30 (d, J=2.1 Hz, 1H), 5.93 (d, J=5.5 Hz, 1H), 5.85 (br. s., 1H),4.82 (s, 2H), 3.91 (s, 3H), 3.02-2.90 (m, 1H), 2.84-2.73 (m, 1H), 2.69(s, 3H) (1 methyl group under DMSO); LC-MS: Method H, RT=1.10 min, MS(ESI) m/z: 464.2 (M+H)⁺; Analytical HPLC Method B: 97% purity.

Example 1742,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol

Intermediate I-9 (20.09 mg, 0.067 mmol) and Intermediate 171B (16.6 mg,0.056 mmol) were dissolved in DMF (558 μL). PdCl₂(dppf)-CH₂Cl₂ (2.73 mg,3.35 μmol) was added and the reaction mixture was degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 33.5 μL, 0.067 mmol)was added and the reaction mixture was degassed for 5 minutes, thensealed and heated to 100° C. in the microwave for 30 minutes. Thereaction mixture was diluted with DMF, filtered, and purified bypreparative HPLC (Method D, 40 to 80% B in 25 minutes) to give Example174 (4.6 mg, 0.0104 mmol, 18.6%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (s,1H), 8.57 (s, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.31 (s, 1H), 7.16 (d,J=6.1 Hz, 1H), 6.24-6.15 (m, 1H), 4.08 (s, 3H), 3.90 (s, 3H), 2.64 (s,3H); LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 436.2 (M+H)⁺;Analytical HPLC Method B: 98% purity.

Example 175 5-(benzofuran-2-yl)-2-methoxy-7-methylquinoxaline

Intermediate I-9A (0.053 g, 0.209 mmol) and benzofuran-2-ylboronic acid(0.051 g, 0.314 mmol) were dissolved in toluene (3.14 mL) and EtOH(1.047 mL). PdCl₂(dppf)-CH₂Cl₂ adduct (10.26 mg, 0.013 mmol) was addedand the reaction mixture was degassed by bubbling with argon for 15minutes. 2 M aqueous Na₂CO₃ (0.126 mL, 0.251 mmol) was added and thereaction mixture was degassed for 5 minutes, then sealed and heated to120° C. in the microwave for 30 minutes. The reaction mixture wasdiluted with EtOAc, filtered through a micron filter, and concentratedin vacuo. The reaction mixture was purified on Prep HPLC using Method Ato yield Example 175 (2.57 mg, 8.41 μmol, 4.02% yield). ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.52 (s, 1H), 8.14 (d, J=1.8 Hz, 1H), 8.08 (s, 1H), 7.67(d, J=7.5 Hz, 1H), 7.63 (d, J=0.8 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.32(td, J=7.7, 1.3 Hz, 1H), 7.25-7.22 (m, 1H), 4.14-4.10 (m, 3H), 2.63 (s,3H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 291.1 (M+H)⁺.Analytical HPLC: Method A, 94.5% purity.

Example 176 Methyl 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate

Intermediate 176A: ethyl5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate

Intermediate I-15B (0.250 g, 0.847 mmol) and benzofuran-2-ylboronic acid(0.137 g, 0.847 mmol) were dissolved in DMF (20 mL). PdCl₂(dppf)-CH₂Cl₂adduct (0.042 g, 0.051 mmol) was added and the reaction mixture wasdegassed by bubbling with argon for 15 minutes. Na₂CO₃ (3 mL, 6.00 mmol)was added and the reaction mixture was degassed for 5 minutes, thensealed and heated to 90° C. in the microwave for 30 minutes. Thereaction mixture was diluted with EtOAc and filtered through a micronfilter and concentrated in vacuo. The reaction mixture was purified byISCO to remove any Pd or ligand based impurities. 40 g column with a0-100% gradient of EtOAc in hexanes was used. Fractions pooled and theresidue was purified on Prep HPLC using Method A to yield Intermediate176A (0.074 g, 0.223 mmol, 26.3% yield) LC-MS: method H, RT=1.20 min, MS(ESI) m/z: 333.0 (M+H)⁺.

Intermediate 176B: 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylicacid

Intermediate 176A (0.050 g, 0.150 mmol) was dissolved in THF (3 mL) andMeOH (0.300 mL). NaOH, 1 N in water (0.500 mL, 0.500 mmol) was added andthe reaction mixture was allowed to stir at room temperature for 18 h.Diluted with 1 N HCl and EtOAc. The layers were separated and theaqueous layer was back extracted with EtOAc (×3). The organic layer waswashed with brine, dried with sodium sulfate, and concentrated underreduced pressure to yield Intermediate 176B (0.046 g, 0.151 mmol, 100%yield) as a yellow solid. Used without further purification in the nextstep. NMR (500 MHz, DMSO-d₆) δ 9.50 (s, 1H), 8.44 (s, 2H), 8.00 (s, 1H),7.82 (d, J=7.4 Hz, 1H), 7.72 (dd, J=8.3, 0.8 Hz, 1H), 7.43 (td, J=7.7,1.4 Hz, 1H), 7.36-7.30 (m, 1H), 2.71 (s, 3H). LC-MS: method H, RT=1.05min, MS (ESI) m/z: 305.1 (M+H)⁺.

Intermediate 176C: 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carbonylchloride

Intermediate 176B (0.046 g, 0.151 mmol) was dissolved in DCM (3 mL) andoxalyl chloride (0.013 mL, 0.151 mmol) was added. DMF (1.170 μl, 0.015mmol) was added and the reaction mixture was allowed to stir at roomtemperature for 30 min. The reaction mixture was concentrated and storedunder vacuum for 1 h. Used without further purification in the nextstep. LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 319.0 (M+H)⁺. Methylester mass observed by LC/MS.

Example 176

Intermediate 176C (0.0125 g, 0.039 mmol) was dissolved in DCM (3 mL).DMAP (0.473 mg, 3.87 μmol), TEA (10.80 μl, 0.077 mmol), and methanol(1.241 mg, 0.039 mmol) were added and the reaction mixture was allowedto stir at room temperature over the weekend. The reaction mixture wasconcentrated. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 50 to 90% B in 10 minutes) togive Example 176 (0.0057 g, 0.017 mmol, 44.8% yield): ¹H NMR (500 MHz,METHANOL-d₄)) δ 9.53 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H),7.68 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H),7.29-7.22 (m, 1H), 3.37 (s, 3H), 2.69 (s, 3H). LC-MS: method H, RT=1.18min, MS (ESI) m/z: 319.1 (M+H)⁺. Analytical HPLC Method B: 97.0% purity.

Example 177 8-(benzofuran-2-yl)-3-methoxy-6-methylquinoline

Intermediate 177A:(Z)-3-((2-bromo-4-methylphenyl)amino)-2-nitroacrylaldehyde

2-Bromo-4-methylaniline (0.380 g, 2.044 mmol) was dissolved inhydrochloric acid, 2 N in water (1 mL) and sodium(Z)-2-nitro-3-oxoprop-1-en-1-olate hydrate (0.321 g, 2.044 mmol) inwater (2.5 mL) was added to the reaction mixture. The reaction mixturewas allowed to stir for 30 min and the solid was collected to yieldIntermediate 177A (0.537 g, 1.884 mmol, 92%). Material carried onwithout further purification in the next step. ¹H NMR (400 MHz,CHLOROFORM-d) δ 12.46 (br. s., 1H), 10.17 (s, 1H), 8.32 (d, J=14.6 Hz,1H), 7.45 (s, 1H), 7.25-7.22 (m, 2H), 2.34 (s, 3H). LC-MS: method H,RT=0.96 min, MS (ESI) m/z: 285.0 (M+H)⁺.

Intermediate 177B: 8-bromo-6-methyl-3-nitroquinoline

Intermediate 177A (0.537 g, 1.884 mmol) and 2-bromo-4-methylanilinehydrochloride (0.419 g, 1.884 mmol) were dissolved in acetic acid (3 mL)and allowed to reflux for 18 h. The reaction mixture was diluted with 1N NaOH, until basic, and EtOAc. The layers were separated and theaqueous layer was back extracted with EtOAc (×3). The combined organiclayer was washed with brine, dried with sodium sulfate, and concentratedunder reduced pressure and was purified on ISCO, 40 g column 0-100%EtOAc in hexanes to yield Intermediate 177B (0.188 g, 0.704 mmol, 37.4%yield) as a yellow solid. LC-MS: method H, RT=0.99 min, MS (ESI) m/z:267.0 (M+H)⁺.

Intermediate 177C: 8-(benzofuran-2-yl)-6-methyl-3-nitroquinoline

Intermediate 177B (0.070 g, 0.262 mmol) and benzofuran-2-ylboronic acid(0.042 g, 0.262 mmol) were dissolved in DMF (20 mL). PdCl₂(dppf)-CH₂Cl₂adduct (0.013 g, 0.016 mmol) was added and the reaction mixture wasdegassed by bubbling with argon for 15 minutes. Na₂CO₃ (0.175 mL, 0.524mmol) was added and the reaction mixture was degassed for 5 minutes,then sealed and heated to 90° C. in the microwave for 30 minutes. Thereaction mixture was diluted with EtOAc and filtered through a micronfilter and concentrated in vacuo. The reaction mixture was purified byISCO 40 g column with a 0-100% gradient of EtOAc in hexanes was used.Combined impure fractions were diluted with DMF, filtered, and purifiedby preparative HPLC (Method D, 55 to 90% B in 10 minutes) to yieldIntermediate 177C (0.0364 g, 0.120 mmol, 45.6% yield): ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.97 (d, J=2.5 Hz, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.29 (d,J=0.8 Hz, 1H), 7.75 (s, 1H), 7.73-7.70 (m, 1H), 7.58 (dd, J=8.3, 0.8 Hz,1H), 7.36 (td, J=7.7, 1.4 Hz, 1H), 7.30-7.27 (m, 1H), 2.69 (s, 3H).LC-MS: method H, RT=1.31 min, MS (ESI) m/z: 304.9 (M+H)⁺. AnalyticalHPLC Method B: 100% purity.

Intermediate 177D: 8-(benzofuran-2-yl)-6-methylquinolin-3-amine

Intermediate 177C (0.031 g, 0.102 mmol) was dissolved in MeOH (5 mL) andPd/C (1.084 mg, 10.19 μmol) was added. The reaction mixture wasevacuated and back filled with argon (×3). The reaction mixture was thenevacuated and back filled with hydrogen (0.205 mg, 0.102 mmol) (×3). Thereaction mixture was allowed to stir at room temperature for 3 hours.The reaction mixture was filtered to remove the Pd/C and concentratedunder reduced pressure to yield Intermediate 177D (0.022 g, 0.080 mmol,79% yield). Used without further purification. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.56 (d, J=2.8 Hz, 1H), 8.17 (d, J=0.8 Hz, 1H), 8.06 (d,J=1.8 Hz, 1H), 7.68-7.64 (m, 1H), 7.55 (dd, J=8.2, 0.6 Hz, 1H), 7.36 (s,1H), 7.32-7.27 (m, 1H), 7.24 (dd, J=7.5, 1.0 Hz, 1H), 7.20 (d, J=2.8 Hz,1H), 3.91 (s, 2H), 2.56 (s, 3H). LC-MS: method H, RT=0.95 min, MS (ESI)m/z: 275.3 (M+H)⁺.

Intermediate 177E: 8-(benzofuran-2-yl)-6-methylquinolin-3-ol

Intermediate 177D (0.0178 g, 0.065 mmol) was dissolved in MeCN (0.468mL) and cooled to 0° C. Tetrafluoroboric acid (9.84 μl, 0.071 mmol) wasadded and stirring continued for 10 minutes. After this time, a solutionof tert-butyl nitrite (8.49 μl, 0.071 mmol) in MeCN (0.047 mL) was addeddropwise and stirring continued for 10 minutes. After this time, thereaction mixture was cooled to −15° C. and water (0.936 mL) was added.This cooled solution was added into a solution of copper(II) nitrate,trihydrate (3.14 g, 12.98 mmol) and copper(I) oxide (0.418 g, 2.92 mmol)in water (9.36 mL), precooled to 0° C. Stirring was continued at thesame temperature for 18 h. The reaction mixture was then extractedthrice with EtOAc. The combined organic extracts were washed with brine,dried with sodium sulfate, filtered through Celite, and concentrated invacuo. The reaction mixture was purified on Prep HPLC Method A to yieldIntermediate 177E 0.018 g, 0.065 mmol, 60%, 65% purity) Used in the nextstep without further purification. LC-MS: method H, RT=1.14 min, MS(ESI) m/z: 276.1 (M+H)⁺.

Example 177

Intermediate 177E (0.018 g, 0.065 mmol) was dissolved in acetone (3 mL)and K₂CO₃ (0.018 g, 0.131 mmol) was added. MeI (8.18 μl, 0.131 mmol) wasadded and the reaction mixture was allowed to stir at room temperaturefor 5h. The reaction mixture was diluted with water and EtOAc. Thelayers were separated and the organic layer was washed with brine, driedwith sodium sulfate, and concentrated under reduced pressure. Thereaction mixture was diluted with DMF, filtered, and purified bypreparative HPLC (Method D, 35 to 85% B in 10 minutes) to give Example177 (0.0032 g, 10.95 μma 16.75% yield): ¹H NMR (500 MHz, METHANOL-d₄) δ8.68 (d, J=2.8 Hz, 1H), 8.12 (d, J=1.7 Hz, 1H), 8.08 (s, 1H), 7.65 (d,J=7.4 Hz, 1H), 7.56-7.53 (m, 2H), 7.46 (d, J=3.0 Hz, 1H), 7.32-7.27 (m,1H), 7.26-7.19 (m, 1H), 3.98 (s, 3H), 2.59 (s, 3H)). LC-MS: method H,RT=1.31 min, MS (ESI) m/z: 290.2 (M+H)⁺. Analytical HPLC Method B: 99%purity.

Example 1782-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole

Intermediate I-1 (0.007 g, 0.028 mmol) and2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole (6.01 mg, 0.028 mmol) weredissolved in DMF (3 mL). PdCl₂(dppf)-CH₂Cl₂ adduct (1.350 mg, 1.654mmol) was added and the reaction mixture was degassed by bubbling withargon for 15 minutes. Na₂CO₃ (0.018 mL, 0.055 mmol) was added and thereaction mixture was degassed for 5 minutes, then sealed and heated to90° C. in the microwave for 30 minutes. The reaction mixture was dilutedwith EtOAc and filtered through a micron filter and concentrated invacuo. The reaction mixture was diluted with DMF, filtered, and purifiedby preparative HPLC (Method D, 50 to 85% B in 10 minutes) to yieldExample 178 (0.0052 g, 0.015 mmol, 54.0% yield): ¹H NMR (500 MHz,METHANOL-d₄) δ 8.64 (s, 1H), 8.43 (d, J=1.7 Hz, 1H), 7.84-7.53 (m, 2H),2.89 (d, J=5.8 Hz, 4H), 2.64 (s, 3H), 2.00-1.87 (m, 4H). LC-MS: methodH, RT=1.26 min, MS (ESI) m/z: 348.0 (M+H)⁺. Analytical HPLC Method B:99% purity.

Example 1795-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine

Intermediate I-9 (10 mg, 0.033 mmol),2-bromo-5-methoxy-7-methylthiazolo[5,4-b]pyridine (10.36 mg, 0.040mmol), and phosphoric acid, potassium salt (14.14 mg, 0.067 mmol) weredissolved in DMF (333 μl) and degassed by bubbling with argon for 15minutes. Pd(Ph₃P)₄ (3.85 mg, 3.33 μmol) was added and degassingcontinued for 5 minutes. The reaction mixture was heated to 85° C. for18 h. The reaction mixture was diluted with DMF, filtered, and purifiedby preparative HPLC (Method D, 60% to 100% B in 20 minutes) to yieldExample 179 (0.0014 g, 3.89 μmol, 11.69% yield): ¹H NMR (500 MHz,CHLOROFORM-d) δ 8.62 (br. s., 1H), 8.56 (br. s., 1H), 7.76 (br. s., 1H),6.72 (br. s., 1H), 4.15 (br. s., 3H), 4.05 (br. s., 3H), 2.81 (br. s.,3H), 2.69 (br. s., 3H). LC-MS: method H, RT=1.57 min, MS (ESI) m/z:353.0 (M+H)⁺. Analytical HPLC Method B: 98% purity.

Example 1806-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine

Intermediate I-2 (955 μl, 0.048 mmol), Intermediate I-17 (15.07 mg,0.057 mmol), and phosphoric acid, potassium salt (20.27 mg, 0.095 mmol)were dissolved in DMF (477 μl) and degassed by bubbling with argon for15 minutes. Pd(Ph₃)₄ (5.52 mg, 4.77 μmol) was added and degassingcontinued for 5 minutes. The reaction mixture was heated to 85° C. for18 h. The reaction mixture was diluted with DMF, filtered, and purifiedby preparative HPLC (Method D, 45% to 75% B in 22 minutes) to yieldExample 180 (2.0 mg, 4.91 μmol, 10.29% yield): ¹H NMR (500 MHz, DMSO-d₆)δ 9.13 (s, 1H), 8.79 (s, 1H), 8.48 (d, J=10.7 Hz, 1H), 8.09 (s, 1H),4.83 (s, 2H), 4.12 (s, 3H), 3.49 (s, 3H), 2.70 (s, 3H). LC-MS: method H,RT=1.39 min, MS (ESI) m/z: 371.1 (M+H)⁺. Analytical HPLC Method B: 91%purity.

Example 1815-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine

Intermediate I-2 (1273 μl, 0.064 mmol), Intermediate I-16 (19.79 mg,0.076 mmol), and phosphoric acid, potassium salt (27.0 mg, 0.127 mmol)were dissolved in DMF (637 μl) and degassed by bubbling with argon for15 minutes. Pd(PPh₃)₄ (7.36 mg, 6.37 μmol) was added and degassingcontinued for 5 minutes. The reaction mixture was heated to 85° C. for18 h. The reaction mixture was diluted with DMF, filtered, and purifiedby preparative HPLC (Method D, 60% to 100% B in 20 minutes) to yieldExample 181 (11 mg, 0.029 mmol, 45.7% yield): ¹H NMR (500 MHz,CHLOROFORM-d) δ 9.06 (s, 1H), 8.82 (d, J=1.7 Hz, 1H), 7.94 (d, J=0.8 Hz,1H), 6.71 (d, J=0.8 Hz, 1H), 4.84 (s, 2H), 4.03 (s, 3H), 3.58 (s, 3H),2.79 (d, J=0.6 Hz, 3H), 2.71 (s, 3H) LC-MS: method H, RT=1.43 min, MS(ESI) m/z: 367.1 (M+H)⁺. Analytical HPLC Method B: 97% purity.

Example 1826-fluoro-5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridine

Intermediate I-1 (0.020 g, 0.067 mmol) and Intermediate I-17 (0.018 g,0.067 mmol) were dissolved in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(3.26 mg, 4.00 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100mL, 0.300 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was filtered and the solid was collected.Recrystallized from DMSO to yield Example 182 (0.0024 g, 6.13 μmol,9.20% yield) as a yellow solid: ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.57(d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.98 (d, J=10.6 Hz, 1H), 7.77 (s, 1H),4.15 (s, 3H), 4.13 (s, 3H), 2.65 (s, 3H). LC-MS: method H, RT=1.52 min,MS (ESI) m/z: 357.1 (M+H)⁺. Analytical HPLC Method A: 91% purity.

Example 1836-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole

Intermediate I-2 (0.025 g, 0.080 mmol) and Intermediate I-3 (0.021 g,0.080 mmol) were dissolved in DMF (3 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(3.90 mg, 4.77 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aq. solution (0.100 mL,0.300 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was diluted with EtOAc and water. Thelayers were separated and the organic layer was washed with brine, driedwith sodium sulfate, and concentrated under reduced pressure. Thereaction mixture was purified on Prep HPLC using Method A yield Example183 (0.021 g, 0.057 mmol, 72.2% yield): ¹H NMR (500 MHz, CHLOROFORM-d) δ9.08 (s, 1H), 8.88 (s, 1H), 7.93 (s, 1H), 7.27-7.26 (m, 1H), 6.94 (s,1H), 4.84 (s, 2H), 3.90 (s, 3H), 3.57 (d, J=0.6 Hz, 3H), 2.84 (s, 3H),2.71 (s, 3H). LC-MS: method H, RT=1.40 min, MS (ESI) m/z: 366.2 (M+H)⁺.Analytical HPLC: Method A, 92.3% purity.

Example 184 5-(benzofuran-2-yl)-2-(1-methoxyethyl)-7-methylquinoxaline

Intermediate 184A: ethyl5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate

Intermediate I-15 (0.650 g, 2.202 mmol) and benzofuran-2-ylboronic acid(0.357 g, 2.202 mmol) were dissolved in DMF (20 mL). PdCl₂(dppf)-CH₂Cl₂adduct (0.108 g, 0.132 mmol) was added and the reaction mixture wasdegassed by bubbling with argon for 15 minutes. 3 M Na₂CO₃ (1.468 mL,4.40 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was diluted with EtOAc and filteredthrough a micron filter and concentrated in vacuo. Purified by ISCO toremove any Pd or ligand based impurities using a 40 g column with a0-100% gradient of EtOAc in hexanes. Fractions pooled and the residuewas purified on Prep HPLC Method A to yield Intermediate 184A (0.117 g,0.352 mmol, 15.98% yield). LC-MS: method H, RT=1.21 min, MS (ESI) m/z:333.1 (M+H).

Intermediate 184B: 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylicacid

Intermediate 184A (0.020 g, 0.060 mmol) was dissolved in THF (3 mL) andMeOH. NaOH, 1 N in water (0.500 mL, 0.500 mmol) was added and thereaction mixture was allowed to stir at room temperature for 18 h.Diluted with 1 N HCl and EtOAc. The layers were separated and theaqueous layer was back extracted with EtOAc (×3). The organic layer waswashed with brine, dried with sodium sulfate, and concentrated underreduced pressure to yield Intermediate 184B (0.017 g, 0.060 mmol, 99%yield) as a yellow solid. Used without further purification in the nextstep. ¹H NMR (500 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.42 (d, J=1.4 Hz, 1H),8.23 (s, 1H), 8.03 (br. s., 1H), 7.81 (d, J=7.4 Hz, 1H), 7.71 (d, J=8.0Hz, 1H), 7.41 (td, J=7.7, 1.4 Hz, 1H), 7.35-7.29 (m, 1H), 2.69 (s, 3H).LC-MS: method H, RT=1.05 min, MS (ESI) m/z: 305.0 (M+H)⁺.

Intermediate 184C: 5-(benzofuran-2-yl)-7-methylquinoxaline-2-carbonylchloride

Intermediate 184B (0.018 g, 0.059 mmol) was dissolved in DCM (3 mL) andoxalyl chloride (5.18 μl, 0.059 mmol) was added. DMF (0.458 μl, 5.92μmol) was added and the reaction mixture was allowed to stir at roomtemperature for 30 min. The reaction was concentrated and stored undervacuum for 1 h to yield Intermediate 184C (0.019 g, 0.059 mmol, 100%yield). Used without further purification in the next step. LC-MS:method H, RT=1.16 min, MS (ESI) m/z: 319.1 (M+H)⁺. Observed mass of themethyl ether in the LC/MS.

Intermediate 184D:5-(benzofuran-2-yl)-N-methoxy-N,7-dimethylquinoxaline-2-carboxamide

Intermediate 184C (0.019 g, 0.059 mmol) was dissolved in DCM (3 mL).DMAP (0.719 mg, 5.89 μmol), TEA (0.016 mL, 0.118 mmol), andN,O-dimethylhydroxylamine hydrochloride (5.74 mg, 0.059 mmol) were addedand the reaction mixture was allowed to stir at room temperature for 18h. The reaction mixture was diluted with water and EtOAc. The layerswere extracted and the aqueous layer was back extracted with EtOAc (×3).The combined organic layer was washed with brine, dried with sodiumsulfate, and concentrated under reduced pressure to yield Intermediate184D (0.021 g, 0.060 mmol, 100% yield) as a yellow solid. Used withoutfurther purification in the next step. NMR (400 MHz, CHLOROFORM-d) δ8.41 (d, J=1.8 Hz, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 7.70 (d, J=7.5 Hz,1H), 7.58 (d, J=8.3 Hz, 1H), 7.40-7.33 (m, 1H), 7.31-7.25 (m, 2H), 3.83(br. s., 3H), 3.48 (d, J=15.6 Hz, 3H), 2.74-2.64 (m, 3H). LC-MS: methodH, RT=1.13 min, MS (ESI) m/z: 348.1 (M+H)⁺.

Intermediate 184E:5-(benzofuran-2-yl)-N-methoxy-N,7-dimethylquinoxaline-2-carboxamide

Intermediate 184D (0.0698 g, 0.201 mmol) was dissolved in THF (2.009 mL)and cooled to 0° C. methylmagnesium bromide (0.067 mL, 0.201 mmol) wasadded and the reaction mixture was allowed to slowly warm to roomtemperature over 3 h. The reaction mixture was diluted with EtOAc and 1N aqueous HCl. The mixture was allowed to stir for 30 min. The layerswere separated and the organic layer was washed with brine, dried withsodium sulfate, and concentrated under reduced pressure. The reactionmixture was purified on Prep HPLC using Method A to yield Intermediate184E (0.0087 g, 0.029 mmol, 14.32% yield) as a yellow solid. ¹H NMR (400MHz, CHLOROFORM-d) δ 9.54 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.23 (d,J=0.8 Hz, 1H), 7.94 (d, J=0.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.58 (d,J=7.5 Hz, 1H), 7.35 (td, J=7.7, 1.3 Hz, 1H), 7.31-7.29 (m, 1H), 2.87 (s,3H), 2.71 (s, 3H). LC-MS: method H, RT=1.25 min, MS (ESI) m/z: 303.1(M+H)⁺.

Intermediate 184F:1-(5-(benzofuran-2-yl)-7-methylquinoxalin-2-yl)ethanol

Intermediate 184E (0.010 g, 0.033 mmol) was dissolved in MeOH (1 mL) andcooled to 0° C. CeCl₃ (0.012 g, 0.033 mmol) was added to the reactionmixture followed by NaBH₄ (5.01 mg, 0.132 mmol). The reaction mixturewas allowed to stir for 1 h. The reaction mixture was diluted withsaturated NH₄Cl solution and EtOAc. The layers were separated and theaqueous layer was back extracted with EtOAc (×3). The combined organiclayer was washed with brine, dried with sodium sulfate, and concentratedunder reduced pressure to yield Intermediate 184F (0.009 g, 0.030 mmol,89% yield). Will be used without further purification. LC-MS: method H,RT=1.23 min, MS (ESI) m/z: 305.1 (M+H)⁺.

Example 184

Intermediate 184F (0.0069 g, 0.023 mmol) was dissolved in DMF and NaH(0.907 mg, 0.023 mmol) was added. The reaction mixture was allowed tostir at room temperature for 10 min and MeI (1.418 μl, 0.023 mmol) wasadded. The reaction mixture was stirred at room temperature for 3h. Thereaction mixture was diluted with water and EtOAc. The layers wereseparated and the organic layer was washed with brine, dried with sodiumsulfate and concentrated under reduced pressure to yield a yellow oil.The reaction mixture was diluted with DMF, filtered, and purified bypreparative HPLC (Method D, 55% to 95% B in 10 minutes) to yield Example184 (0.0005 g, 1.571 μmol, 6.93% yield): ¹H NMR (500 MHz, METHANOL-d₄) δ9.07 (s, 1H), 8.34 (d, J=1.7 Hz, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.68(d, J=7.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.36-7.31 (m, 1H), 7.27-7.23(m, 1H), 4.69 (q, J=6.8 Hz, 1H), 3.42 (s, 3H), 2.68 (s, 3H), 1.62 (d,J=6.6 Hz, 3H). LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 319.1 (M+H)⁺.Analytical HPLC Method B: 100% purity.

Example 1856-methoxy-2-(3-(methoxymethyl)-6-methylquinolin-8-yl)-4-methylbenzo[d]thiazole

Intermediate 185A: methyl 8-bromo-6-methylquinoline-3-carboxylate

8-bromo-6-methylquinoline-3-carboxylic acid (250 mg, 0.940 mmol) wasdissolved in MeOH (3758 μl). Thionyl chloride (206 μl, 2.82 mmol) wasadded and the reaction mixture was heated to reflux for 4h. The reactionmixture was cooled to ambient temperature and concentrated in vacuo toyield Intermediate 185A (0.263 g, 0.940 mmol, 100% yield): ¹H NMR (400MHz, CHLOROFORM-d) δ 9.52 (d, J=2.0 Hz, 1H), 8.80 (d, J=1.8 Hz, 1H),8.06 (d, J=1.5 Hz, 1H), 7.70 (s, 1H), 4.06 (s, 3H), 2.59 (s, 3H). LC-MS:method H, RT=1.14 min, MS (ESI) m/z: 280/282 (M+H)⁺.

Intermediate 185B: (8-bromo-6-methylquinolin-3-yl)methanol

NaBH₄ (70.2 mg, 1.856 mmol) and calcium chloride (103 mg, 0.928 mmol)were dissolved in THF (2750 μl). A solution of Intermediate 185A (260mg, 0.928 mmol) in THF (688 μl) was added dropwise. The reaction mixturewas allowed to stir for 18 h. The reaction mixture was diluted withEtOAc, washed with water, then brine, dried sodium sulfate, filtered,and concentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0to 100% EtOAc in hexanes) to yield Intermediate 185B (0.146 g, 0.579mmol, 62% yield): ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.97 (d, J=1.8 Hz,1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.58 (s, 1H), 4.97 (d, J=5.5 Hz, 2H),2.55 (s, 3H), 1.93 (t, J=5.7 Hz, 1H). LC-MS: method H, RT=0.85 min, MS(ESI) m/z: 252/254 (M+H)⁺.

Intermediate 185C: (8-bromo-6-methylquinolin-3-yl)methylmethanesulfonate

Intermediate 185B (146 mg, 0.579 mmol) and TEA (242 μl, 1.737 mmol) weredissolved in DCM (16 mL). Methanesulfonic anhydride (121 mg, 0.695 mmol)was added and the reaction mixture was allowed to stir at roomtemperature for 3h. The reaction mixture was diluted with DCM and washedwith saturated NaHCO₃, dried sodium sulfate, filtered, and concentratedin vacuo to yield Intermediate 185C (0.191 g, 0.579 mmol, 100% yield).The material will be used crude in the next step. LC-MS: method H,RT=1.03 min, MS (ESI) m/z: 330.0 (M+H)⁺.

Intermediate 185D: 8-bromo-3-(methoxymethyl)-6-methylquinoline

Intermediate 185C (190 mg, 0.575 mmol) was dissolved in THF (12 mL). 0.5M sodium methoxide (2302 μl, 1.151 mmol) and the reaction mixture wasallowed to stir for 18 h. The reaction mixture was concentrated in vacuoto remove the THF, diluted with EtOAc and washed with 0.5 N HCl, thenbrine, dried sodium sulfate, filtered, and concentrated in vacuo toyield Intermediate 185D (0.100 g, 0.376 mmol, 65% yield): ¹H NMR (400MHz, CHLOROFORM-d) δ 8.94 (d, J=2.0 Hz, 1H), 8.07-8.03 (m, 1H), 7.93 (d,J=1.8 Hz, 1H), 7.57 (s, 1H), 4.69 (s, 2H), 3.49 (s, 3H), 2.55 (s, 3H).LC-MS: method H, RT=1.00 min, MS (ESI) m/z: 266.0 (M+H)⁺.

Intermediate 185E: (3-(methoxymethyl)-6-methylquinolin-8-yl)boronic acid

Intermediate 185D (100 mg, 0.376 mmol), bis(pinacolato)diboron (143 mg,0.564 mmol), and potassium acetate (92 mg, 0.939 mmol) were dissolved indioxane (2099 μl) and degassed for 5 minutes by bubbling with argon.PdCl₂(dppf)-CH₂Cl₂ adduct (24.55 mg, 0.030 mmol) was added and thereaction mixture was degassed for an additional 10 minutes. The reactionmixture was heated to 130° C. in the microwave for 45 minutes. Thereaction mixture was then diluted with EtOAc and water. The reactionmixture was further extracted twice with EtOAc. The combined organiclayers were washed with brine, dried sodium sulfate, filtered, andconcentrated in vacuo. The crude material was purified by Prep LC (AxiaLuna 5 u C18 30×100 mm column, 12 minute gradient from 30 to 100% B inA, A=10:90:0.1 MeOH:H₂O:TFA, B=90:10:0.1 MeOH:H₂O:TFA) to yieldIntermediate 185E (0.063 g, 0.240 mmol, 64% yield): LC-MS: method H,RT=0.75 min, MS (ESI) m/z: 232.1 (M+H)⁺ (see mass of methyl boronicester in the LC/MS).

Example 185

Intermediate 185E (0.025 g, 0.096 mmol) and Intermediate I-3 (0.025 g,0.096 mmol) were dissolved in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(4.73 mg, 5.79 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aq. solution (0.030 mL,0.090 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 30% to 70% B in 10 minutes) toyield Example 185 (0.0097 g, 0.026 mmol, 27.0% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 9.00 (d, J=1.9 Hz, 1H), 8.80 (d, J=1.4 Hz, 1H), 8.36 (s, 1H),7.95 (s, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.00 (d, J=1.4 Hz, 1H), 4.71 (s,2H), 3.86 (s, 3H), 3.42 (s, 3H), 2.76 (s, 3H), 2.65 (s, 3H). LC-MS:method H, RT=1.22 min, MS (ESI) m/z: 365.3 (M+H)⁺. Analytical HPLCMethod B: 98% purity.

Example 1862-(2-(difluoro(methoxy)methyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole

Intermediate 186A: O-methyl 5-bromo-7-methylquinoxaline-2-carbothioate

Methyl 5-bromo-7-methylquinoxaline-2-carboxylate (0.200 g, 0.711 mmol)was dissolved in o-xylenes (2.85 mL) and Lawesson's Reagent (0.576 g,1.423 mmol) was added. The reaction mixture was heated to reflux for 18h. The reaction mixture was filtered and the filter cake washed witho-xylenes. o-Xylenes solution was loaded directly on the ISCO column.The reaction mixture was purified on ISCO 40 g column 0-50% EtOAc inhexanes gradient to yield Intermediate 186A (0.005 g, 0.017 mmol, 2.365%yield) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.78 (s, 1H),8.07 (d, J=1.8 Hz, 1H), 8.04 (d, J=0.9 Hz, 1H), 4.49 (s, 3H), 2.64 (s,3H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 296.9 (M+H)⁺.

Intermediate 186B:5-bromo-2-(difluoro(methoxy)methyl)-7-methylquinoxaline

Intermediate 186A (0.068 g, 0.229 mmol) was dissolved in CH₂Cl₂.Bis-(2-methoxyethyl)aminosulfur trifluoride (0.084 mL, 0.458 mmol) wasadded and the reaction mixture was allowed to stir at room temperaturefor 48h. The reaction mixture was diluted with EtOAc and water. Theorganic layer was washed with sodium bicarbonate, washed with brine,dried with sodium sulfate, and concentrated under reduced pressure toyield Intermediate 186B (0.065 g, 0.214 mmol, 94% yield) a yellow oil.¹H NMR (400 MHz, CHLOROFORM-d) δ 9.21 (s, 1H), 8.08 (d, J=1.8 Hz, 1H),8.01 (s, 1H), 3.91 (s, 3H), 2.64 (s, 3H). LC-MS: method H, RT=1.29 min,MS (ESI) m/z: 302.9 (M+H)⁺.

Intermediate 186C:(2-(difluoro(methoxy)methyl)-7-methylquinoxalin-5-yl)boronic acid

A mixture of Intermediate 186B (0.070 g, 0.231 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.088 g,0.346 mmol), potassium acetate (0.057 g, 0.577 mmol) in dioxane (2.309mL) were degassed by bubbling argon for 5 min. PdCl₂(dppf)-CH₂Cl₂ adduct(9.43 mg, 0.012 mmol) was added and the mixture was sealed and heated inmicrowave at 130° C. for 30 min. The reaction mixture was diluted withwater and EtOAc. The layers were separated and the organic layer waswashed with water, washed with brine, dried with sodium sulfate, andconcentrated under reduced pressure. The reaction mixture was purifiedon Prep HPLC using Method A to yield Intermediate 186C (0.010 g, 0.037mmol, 16.16% yield) as a brown solid. LC-MS: method H, RT=0.88 min, MS(ESI) m/z: 269.1 (M+H)⁺.

Example 186

Intermediate 186C (0.010 g, 0.029 mmol) and Intermediate I-3 (7.37 mg,0.029 mmol) were dissolved in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(1.399 mg, 1.713 μmol) was added and the reaction mixture was degassedby bubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution(0.050 mL, 0.150 mmol) was added and the reaction mixture was degassedfor 5 minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 55% to 100% B in 20 minutes) toyield Example 186 (0.0064 g, 0.016 mmol, 55.8% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 9.36 (s, 1H), 8.93 (s, 1H), 8.17 (s, 1H), 7.56 (d, J=2.2 Hz,1H), 7.02 (d, J=1.1 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 2.76 (s, 3H),2.73 (s, 3H). LC-MS: method H, RT=1.50 min, M/S (ESI) m/z: 402.1 (M+H)⁺.Analytical HPLC Method B: 100% purity.

Example 1876-methoxy-4-methyl-2-(7-methyl-2-(phenoxymethyl)quinoxalin-5-yl)benzo[d]thiazole

Intermediate 187A: 1-diazo-3-phenoxypropan-2-one

To 2-phenoxyacetyl chloride (0.250 g, 1.465 mmol) in MeCN cooled withice-bath was added (diazomethyl)trimethylsilane 2.0 M in diethyl ether(1.282 mL, 2.56 mmol). The mixture was allowed to stir at roomtemperature for 3h. Solvent was removed under reduced pressure. Thecrude product was purified by flash chromatography (loading inchloroform, 0% to 50% EtOAc in hexane over 18 min using a 40 g silicagel cartridge). The desired fractions were combined and concentrated(bath temp below 35° C.) to yield Intermediate 187A (0.215 g, 1.220mmol, 83% yield) as a pale yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.32 (t, J=8.0 Hz, 2H), 7.03 (t, J=7.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 2H),5.82 (s, 1H), 4.55 (s, 2H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z:177.1 (M+H)⁺.

Intermediate 187B: 1-bromo-3-phenoxypropan-2-one

Intermediate 187A (0.215 g, 1.220 mmol) was dissolved in Et₂O (4.88 mL)and the mixture was cooled to 0° C. and HBr (0.242 mL, 2.136 mmol) wasadded dropwise. After 5 min at 0° C., the reaction mixture was allowedto stir at room temperature for 10 min. The reaction mixture was dilutedwith ether, washed with saturated aqueous sodium bicarbonate, washedwith brine, and dried over sodium sulfate. The organic layer wasconcentrated (kept bath below 30° C.) and the product was usedimmediately without further purification. Intermediate 187B (0.224 g,0.978 mmol, 80% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.33 (t, J=7.9Hz, 2H), 7.03 (t, J=7.4 Hz, 1H), 6.91 (d, J=8.1 Hz, 2H), 4.79 (s, 2H),4.18 (s, 2H). LC-MS: method H, RT=1.09 min, Compound does not ionizewell.

Intermediate 187C: 5-bromo-7-methyl-2-(phenoxymethyl)quinoxaline

To Intermediate I-1B (0.300 g, 0.906 mmol) in anhydrous DMF (30 mL) at0° C. was added cesium carbonate (0.516 g, 1.585 mmol) in severalportions. The brown solution was stirred at 0° C. for 10 min, followedby addition of Intermediate 187B (0.249 g, 1.087 mmol) in DMF (5.0 mL).The brown solution turned yellow. The mixture was stirred at roomtemperature for 18 h. The mixture was diluted with EtOAc, washed withwater, brine, dried over sodium sulfate and concentrated. The residuewas dissolved in ethyl acetate (8 mL) and 4.0 N HCl in dioxane (1.170mL, 4.68 mmol) was added. The mixture was stirred at room temperaturefor 45 min. Solvent was removed under vacuum to give the deprotectedintermediate as a yellow oil. The deprotected intermediate was dissolvedin THF (20 mL). Tin(II) chloride dihydrate (0.290 g, 1.287 mmol) wasadded, followed by concentrated HCl (0.048 mL, 0.585 mmol). The mixturewas placed and stirred in an oil bath pre-heated at 45° C. for 18 h. Thereaction mixture was diluted with EtOAc/water and neutralized withsaturated sodium bicarbonate. The mixture was stirred at roomtemperature for 15 min, the precipitate was removed by filtration. Theorganic layer was washed with saturated sodium bicarbonate, washed withbrine, dried over sodium sulfate, and concentrated. The reaction mixturewas purified on ISCO, 24 g column 0-100% EtOAc in hexanes to giveIntermediate 187C (0.093 g, 0.254 mmol, 65.2% yield) as a light yellowsolid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.13 (s, 1H), 7.95 (d, J=1.5 Hz,1H), 7.83 (s, 1H), 7.36-7.28 (m, 2H), 7.06-6.95 (m, 3H), 5.44 (s, 2H),2.60 (s, 3H). LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 329.1 (M+H)⁺.

Intermediate 187D:7-methyl-2-(phenoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

A mixture of Intermediate 187C (0.093 g, 0.283 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.108 g,0.424 mmol), potassium acetate (0.069 g, 0.706 mmol) in dioxane (2.83mL) were degassed by bubbling argon for 5 min. PdCl₂(dppf)-CH₂Cl₂ adduct(0.012 g, 0.014 mmol) was added and the mixture was sealed and heated inmicrowave at 130° C. for 30 min. The reaction mixture was diluted withwater and EtOAc. The layers were separated and the organic layer waswashed with water, washed with brine, dried with sodium sulfate, andconcentrated under reduced pressure to yield Intermediate 187D (0.100 g,0.266 mmol, 94% yield). Used without further purification. LC-MS: methodH, RT=1.21 min, MS (ESI) m/z: 295.2 (M+H)+(Mass of the boronic acid wasobserved in LC/MS).

Example 187

Intermediate 187D (0.025 g, 0.066 mmol) and2-bromo-6-methoxy-4-methylbenzo[d]thiazole (0.017 g, 0.066 mmol) weredissolved in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct (3.26 mg, 3.99 μmol)was added and the reaction mixture was degassed by bubbling with argonfor 15 minutes. 3 M aqueous sodium bicarbonate solution (0.022 mL, 0.066mmol) was added and the reaction mixture was degassed for 5 minutes,then sealed and heated to 90° C. in the microwave for 30 minutes. Thereaction mixture was filtered and concentrated. The reaction mixture wasdiluted with DMF, filtered, and purified by preparative HPLC (Method D,55% to 100% B in 20 minutes) to yield Example 187 (0.0084 g, 0.019 mmol,28.7% yield): ¹H NMR (500 MHz, CHLOROFORM-d) δ 9.22 (s, 1H), 8.93 (s,1H), 7.97 (s, 1H), 7.36 (t, J=7.8 Hz, 2H), 7.28 (d, J=2.5 Hz, 1H), 7.10(d, J=8.3 Hz, 2H), 7.05 (t, J=7.3 Hz, 1H), 6.97 (s, 1H), 5.49 (s, 2H),3.93 (s, 3H), 2.87 (s, 3H), 2.76 (s, 3H). LC-MS: method H, RT=1.53 min,MS (ESI) m/z: 428.2 (M+H)⁺. Analytical HPLC Method B: 97% purity.

Example 1881-(5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)-N,N-dimethylmethanamine

Intermediate 188A: Ethyl5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxaline-2-carboxylate

Intermediate I-15 (0.030 g, 0.104 mmol) and Intermediate I-3 (0.027 g,0.104 mmol) were dissolved in DMF (3 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(5.10 mg, 6.25 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100mL, 0.300 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was diluted with water and EtOAc. Thelayers were separated and the organic layer was washed with brine, driedwith sodium sulfate, and concentrated under reduced pressure to yield ablack oil. The reaction mixture was purified on ISCO 12 g column 0-100%EtOAc in hexanes to yield Intermediate 188A (0.026 g, 0.066 mmol, 63.5%yield) as a yellow solid. ¹H NMR (500 MHz, CHLOROFORM-d) δ 9.62 (s, 1H),9.02 (s, 1H), 8.16 (s, 1H), 7.28-7.27 (m, 1H), 6.95 (s, 1H), 4.62 (q,J=7.2 Hz, 2H), 3.91 (s, 3H), 2.84 (s, 3H), 2.74 (s, 3H), 1.51 (br. s.,3H), 1.53-1.51 (m, 3H). LC-MS: method H, RT=1.41 min, MS (ESI) m/z:394.1 (M+H)⁺.

Intermediate 188B:(5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)methanol

Sodium borohydride (4.92 mg, 0.130 mmol) and calcium chloride (7.22 mg,0.065 mmol) were dissolved in tetrahydrofuran (2 mL) and allowed to stirfor 1 h. To this suspension was added Intermediate 188A (0.0256 g, 0.065mmol) and the reaction mixture was allowed to stir at room temperaturefor 18 h. The reaction mixture diluted with water and EtOAc. The layerwere separated and the organic layer was washed with brine, dried withsodium sulfate, and concentrated under reduced pressure to yieldIntermediate 188B (0.025 g, 0.071 mmol, 109% yield) as a yellow oil. ¹HNMR (400 MHz, CHLOROFORM-d) δ 8.94 (s, 1H), 8.91 (d, J=1.8 Hz, 1H), 7.98(d, J=0.9 Hz, 1H), 7.31-7.30 (m, 1H), 6.97 (dd, J=2.5, 0.8 Hz, 1H), 5.10(s, 2H), 3.93 (s, 3H), 2.87 (s, 3H), 2.75 (s, 3H). LC-MS: method H,RT=1.29 min, MS (ESI) m/z: 352.1 (M+H)⁺.

Intermediate 188C:(5-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-7-methylquinoxalin-2-yl)methylmethanesulfonate

Intermediate 188B (0.025 g, 0.071 mmol) was dissolved in DCM (3 mL) andtreated with TEA (0.030 mL, 0.213 mmol). To this solution was addedmethanesulfonic anhydride (0.015 g, 0.085 mmol) and the reaction mixturewas allowed to stir at room temperature for 1 h. The reaction mixturewas diluted with EtOAc and saturated sodium bicarbonate. The layers wereseparated and the organic layer was washed with brine, dried with sodiumsulfate and concentrated under reduced pressure to yield Intermediate188C (0.027 g, 0.063 mmol, 88% yield). Used in next step to withoutfurther purification. LC-MS: method H, RT=1.34 min, MS (ESI) m/z: 430.1(M+H)⁺.

Example 188

Intermediate 188C (0.0125 g, 0.029 mmol) was dissolved intetrahydrofuran (0.291 mL) and DIEA (7.62 μl, 0.044 mmol) was added. Tothe stirred reaction mixture was added dimethylamine (7.37 μl, 0.146mmol) and the reaction mixture was allowed to stir at room temperaturefor 18 h. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 45% to 85% B in 18 minutes) toyield Example 188 (1.7 mg, 4.22 μmol, 14.51% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 9.09 (s, 1H), 8.79 (d, J=1.7 Hz, 1H), 8.02 (d, J=0.8 Hz, 1H),7.56 (d, J=2.5 Hz, 1H), 7.01 (d, J=1.7 Hz, 1H), 3.86 (s, 3H), 3.35 (s,2H), 2.76 (s, 3H), 2.69 (s, 3H), 2.33 (s, 6H). LC-MS: method H, RT=1.10min, MS (ESI) m/z: 379.2 (M+H)⁺. Analytical HPLC Method B: 94% purity.

Example 1892-(2-(ethoxymethyl)-7-methylquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole

Intermediate 189A: 1-diazo-3-ethoxypropan-2-one

To 2-ethoxyacetyl chloride (0.250 g, 2.040 mmol) in MeCN cooled withice-bath was added (diazomethyl)trimethylsilane 2.0 M in diethyl ether(1.785 mL, 3.57 mmol). The mixture was allowed to stir at roomtemperature for 3h. Solvent was removed under reduced pressure. Thecrude product was purified by flash chromatography (loading inchloroform, 0% to 50% EtOAc in hexane over 18 min using a 40 g silicagel cartridge). The desired fractions were combined and concentrated(bath temp below 35° C.) to yield Intermediate 189A (0.181 g, 1.413mmol, 69.2% yield) as a pale yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d)δ 5.77 (s, 1H), 3.99 (s, 2H), 3.56 (q, J=6.9 Hz, 2H), 1.25 (t, J=7.0 Hz,3H).

Intermediate 189B: 1-diazo-3-ethoxypropan-2-one

Intermediate 189A (0.145 g, 1.132 mmol) was dissolved in Et₂O (4.53 mL)and cooled to 0° C. and HBr (0.224 mL, 1.980 mmol) was added dropwise.After 5 min at 0° C., the reaction mixture was allowed to stir at roomtemperature for 10 min. The reaction mixture was diluted with ether,washed with saturated sodium bicarbonate, washed with brine, and driedover sodium sulfate. The organic layer was concentrated (kept bath below30° C.) and the product was used immediately without furtherpurification. Intermediate 189B (0.148 g, 0.818 mmol, 72.2% yield). ¹HNMR (400 MHz, CHLOROFORM-d) δ 4.26 (s, 2H), 4.07 (s, 2H), 3.59 (q, J=6.9Hz, 2H), 1.27 (t, J=6.9 Hz, 3H).

Intermediate 189C: tert-butyl(2-bromo-4-methyl-6-nitrophenyl)(3-ethoxy-2-oxopropyl)carbamate

To Intermediate I-1B (0.226 g, 0.681 mmol) in anhydrous DMF (30 mL) at0° C. was added cesium carbonate (0.388 g, 1.192 mmol) in several parts.The brown solution was stirred at 0° C. for 10 min, followed by additionof Intermediate 189B (0.148 g, 0.818 mmol) in DMF (5.0 mL). The brownsolution turned yellow. The mixture was stirred at room temperature for18 h. The mixture was diluted with EtOAc, washed with water, brine,dried over sodium sulfate and concentrated. The crude product waspurified by ISCO (40 g silica gel column, (0% to 60% EtOAc/Hexane over18 min) to yield Intermediate 189C (0.197 g, 0.457 mmol, 67.0% yield) asa yellow solid. LC-MS: method H, RT=1.22 min, MS (ESI) m/z: 431.0(M+H)⁺.

Intermediate 189D: 5-bromo-2-(ethoxymethyl)-7-methylquinoxaline

To Intermediate 189C (0.187 g, 0.434 mmol) in Ethyl acetate (8 mL) wasadded 4.0 N HCl in dioxane (1.301 mL, 5.20 mmol) and the mixture wasstirred at room temperature for 45 min. Solvent was removed under vacuumto give the deprotected intermediate as a yellow oil. The deprotectedintermediate was dissolved in THF (20 mL). Tin(II) chloride dihydrate(0.323 g, 1.431 mmol) was added, followed by concentrated HCl (0.053 mL,0.650 mmol). The mixture was placed and stirred in an oil bathpre-heated at 45° C. for 18 h. The reaction mixture was diluted withEtOAc/water and neutralized with saturated sodium bicarbonate. Themixture was stirred at room temperature for 15 min, the precipitate wasremoved by a separatory funnel. The organic layer was washed withsaturated sodium bicarbonate, washed with brine, dried over sodiumsulfate and concentrated. The reaction mixture was purified on ISCO 24 gcolumn 0-100% EtOAc in hexanes to yield Intermediate 189D (0.056 g,0.199 mmol, 45.9% yield): ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.05 (s, 1H),7.93 (d, J=1.8 Hz, 1H), 7.81 (s, 1H), 4.86 (s, 2H), 3.68 (q, J=7.0 Hz,2H), 2.58 (s, 3H), 1.31 (t, J=6.9 Hz, 3H). LC-MS: method H, RT=1.20 min,MS (ESI) m/z: 281.1 (M+H)⁺.

Intermediate 189E:2-(ethoxymethyl)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

A mixture of Intermediate 189D (0.056 g, 0.199 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.076 g,0.299 mmol), potassium acetate (0.049 g, 0.498 mmol) in dioxane (1.992mL) were degassed by bubbling argon for 5 min. PdCl₂(dppf)-CH₂Cl₂ adduct(8.13 mg, 9.96 μmol) was added and the mixture was sealed and heated inmicrowave at 130° C. for 30 min. The reaction mixture was diluted withwater and EtOAc. The layers were separated and the organic layer waswashed with water, washed with brine, dried with sodium sulfate, andconcentrated under reduced pressure to yield Intermediate 189E (0.050 g,0.152 mmol, 76% yield) as a brown oil Used without further purificationin the next step. LC-MS: method H, RT=1.06 min, MS (ESI) m/z: 247.2(M+H)⁺. Mass of the boronic acid seen in LC/MS.

Example 189

Intermediate 189E (0.025 g, 0.076 mmol) and Intermediate I-3 (0.020 g,0.076 mmol) were dissolved in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(3.73 mg, 4.57 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. 3 M sodium carbonate solution (0.025mL, 0.076 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was filtered and concentrated. Thereaction mixture was diluted with DMF, filtered, and purified bypreparative HPLC (Method D, 55% to 100% B in 20 minutes) to yieldExample 189 (0.0003 g, 0.759 μmol, 0.996% yield): ¹H NMR (500 MHz,CHLOROFORM-d) δ 9.15 (s, 1H), 8.90 (d, J=1.4 Hz, 1H), 7.95 (s, 1H),7.31-7.30 (m, 1H), 6.97 (s, 1H), 4.91 (s, 2H), 3.93 (s, 3H), 3.76 (q,J=6.9 Hz, 2H), 2.87 (s, 3H), 2.74 (s, 3H), 1.37 (t, J=6.9 Hz, 3H).LC-MS: method H, RT=1.49 min, MS (ESI) m/z: 380.2 (M+H)⁺. AnalyticalHPLC Method B: 96% purity.

Example 1906-methoxy-2-(4-methoxy-3-(methoxymethyl)-6-methylquinolin-8-yl)-4-methylbenzo[d]thiazole

Intermediate 190A: diethyl2-(((2-bromo-4-methylphenyl)amino)methylene)malonate

2-bromo-4-methylaniline (0.667 mL, 5.37 mmol) and diethyl 2-(ethoxymethylene)malonate (1.184 mL, 5.91 mmol) were heated to 100° C. under astream of argon. The reaction mixture stirred for 2h and was cooled toambient temperature, diluted with hexanes, heated gently to break up thematerial, and the solid collected by suction filtration Intermediate190A (1.80 g, 5.05 mmol, 94% yield): ¹H NMR (400 MHz, CHLOROFORM-d) δ11.22 (d, J=12.8 Hz, 1H), 8.48 (d, J=13.4 Hz, 1H), 7.42 (s, 1H),7.21-7.11 (m, 2H), 4.35 (q, J=7.3 Hz, 2H), 4.26 (q, J=7.0 Hz, 2H), 1.39(t, J=7.2 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H).

Intermediate 190B: ethyl8-bromo-4-hydroxy-6-methylquinoline-3-carboxylate

Intermediate 190A (0.250 g, 0.702 mmol) was dissolved in biphenyl ether(12.5 mL) was added. The reaction mixture was stirred at 250° C. for 18h. The reaction mixture was cooled to ambient temperature. The reactionmixture was filtered and washed with Et₂O to yield Intermediate 190B(0.187 g, 0.603 mmol, 86% yield) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 12.33 (s, 1H), 9.19 (s, 1H), 8.09 (s, 1H), 7.99 (d,J=1.5 Hz, 1H), 4.52 (q, J=7.0 Hz, 2H), 2.54 (s, 3H), 1.48 (t, J=7.0 Hz,3H). LC-MS: method H, RT=0.95 min, MS (ESI) m/z: 310.0 (M+H)⁺.

Intermediate 190C: ethyl8-bromo-4-chloro-6-methylquinoline-3-carboxylate

Intermediate 190B (0.100 g, 0.322 mmol) was dissolved in POCl₃ (0.150mL, 1.612 mmol) and heated to reflux for 3h. The reaction mixture wascarefully diluted with water and ice. The layers were separated and theorganic layer was washed with aqueous saturated NaHCO₃, brine, driedwith sodium sulfate, and concentrated under reduced pressure to yieldIntermediate 190C (0.048 g, 0.146 mmol, 45.3% yield) as a pale yellowsolid. Used without further purification in the next step. ¹H NMR (400MHz, CHLOROFORM-d) δ 9.61 (s, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 4.60 (q,J=7.2 Hz, 2H), 2.75 (s, 3H), 1.51 (t, J=7.2 Hz, 3H). LC-MS: method H,RT=1.28 min, MS (ESI) m/z: 328.0 (M+H)⁺.

Intermediate 190D: methyl8-bromo-4-methoxy-6-methylquinoline-3-carboxylate

Intermediate 190C (0.480 g, 1.461 mmol) was dissolved in THF (10 mL) andsodium methoxide (8.76 mL, 4.38 mmol) was added. The reaction mixturewas allowed to stir at room temperature for 30 min. The reaction mixturewas diluted with water and EtOAc. The layers were separated and theorganic layer was washed with brine, dried with sodium sulfate, andconcentrated under reduced pressure to yield Intermediate 190D (0.454 g,1.464 mmol, 100% yield) as a white solid: ¹H NMR (400 MHz, CHLOROFORM-d)δ 9.21 (s, 1H), 8.02 (dd, J=1.8, 0.9 Hz, 1H), 7.98 (d, J=1.8 Hz, 1H),4.14 (s, 3H), 4.01 (s, 3H), 2.55 (s, 3H). LC-MS: method H, RT=1.16 min,MS (ESI) m/z: 310.0 (M+H)⁺.

Intermediate 190E: (8-bromo-4-methoxy-6-methylquinolin-3-yl)methanol

Calcium chloride (0.072 g, 0.645 mmol) and sodium borohydride (0.049 g,1.290 mmol) were suspended in tetrahydrofuran and allowed to stir for 1h. To the stirred reaction mixture was added Intermediate 190D (0.200 g,0.645 mmol) in tetrahydrofuran (25 mL) and the reaction mixture wasallowed to stir for 3 days. The reaction mixture was diluted with waterand EtOAc. The layers were separated and the organic layer was washedwith brine, dried with sodium sulfate, and concentrated under reducedpressure. The reaction mixture was purified by ISCO 24 g column 0-100%EtOAc in hexanes to yield Intermediate 190E (0.050 g, 0.177 mmol, 27.5%yield) as a white solid. ¹H NMR (500 MHz, CHLOROFORM-d) δ 8.96 (s, 1H),7.91 (d, J=1.4 Hz, 1H), 7.85 (d, J=0.8 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H),4.11 (d, J=0.8 Hz, 3H), 2.55 (s, 3H). LC-MS: method H, RT=0.84 min, MS(ESI) m/z: 282.1 (M+H)⁺.

Intermediate 190F: (8-bromo-4-methoxy-6-methylquinolin-3-yl)methylmethanesulfonate

Intermediate 190E (0.050 g, 0.177 mmol) was dissolved in DCM (3 mL) andtreated with TEA (0.074 mL, 0.532 mmol). To this solution was addedmethanesulfonic acid (0.037 g, 0.213 mmol), and the reaction mixture wasallowed to stir at room temperature for 1 h. The reaction mixture wasdiluted with EtOAc and saturated sodium bicarbonate. The layers wereseparated and the organic layer was washed with brine, dried with sodiumsulfate and concentrated under reduced pressure to yield Intermediate190F (0.027 g, 0.073 mmol, 53%). Used without further purification inthe next step. LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 296.1 (M+H)⁺Observed the methyl ether in LC/MS.

Intermediate 190G: 8-bromo-4-methoxy-3-(methoxymethyl)-6-methylquinoline

Intermediate 190F (0.180 g, 0.500 mmol) was dissolved in THF (5.00 ml)and DIPEA (0.131 ml, 0.750 mmol) was added. To the stirred reaction wasadded sodium methoxide (5.00 ml, 2.498 mmol), and the reaction wasallowed to stir at room temperature overnight. The reaction was dilutedwith water and EtOAc. The layers were separated, and the organic layerwas washed with brine, dried with sodium sulfate, and concentrated underreduced pressure to yield Intermediate 190G (0.068 g, 0.230 mmol, 46%)as a yellow solid. Used without further purification in the next step.LC-MS: method H, RT=0.97 min, MS (ESI) m/z: 298.1 (M+H)⁺.

Intermediate 190H:4-methoxy-3-(methoxymethyl)-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

A mixture of Intermediate 190G (0.027 g, 0.091 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.035 g,0.137 mmol), potassium acetate (0.022 g, 0.228 mmol) in dioxane (0.912mL) were degassed by bubbling argon for 5 min. PdCl₂(dppf)-CH₂Cl₂ adduct(3.72 mg, 4.56 μmol) was added and the mixture was sealed and heated inmicrowave at 130° C. for 30 min. The reaction mixture was diluted withwater and EtOAc. The layers were separated and the organic layer waswashed with brine, dried with sodium sulfate, and concentrated underreduced pressure to yield Intermediate 190H (0.040, 0.058, 64%) as abrown oil. Used in the next step without further purification. LC-MS:method H, RT=0.98 min, MS (ESI) m/z: 262.2 (M+H)⁺. Mass of the boronicacid was seen in LC/MS.

Example 190

Intermediate 190H (0.031 g, 0.090 mmol) and Intermediate I-3 (0.023 g,0.090 mmol) were dissolved in DMF (3 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(4.43 mg, 5.42 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100mL, 0.300 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was filtered and concentrated. Thereaction mixture was diluted with DMF, filtered, and purified bypreparative HPLC (Method D, 55% to 100% B in 22 minutes) to yieldExample 190 (0.0036 g, 8.58 μmol, 9.50% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 8.98 (s, 1H), 8.82 (s, 1H), 8.10 (s, 1H), 7.54 (d, J=1.9 Hz,1H), 7.00 (s, 1H), 4.73 (s, 2H), 4.12 (s, 3H), 3.86 (s, 3H), 3.42 (s,3H), 2.76 (s, 3H), 2.68 (s, 3H). LC-MS: method H, RT=1.10 min, MS (ESI)m/z: 395.2 (M+H)⁺. Analytical HPLC Method B: 94% purity.

Example 1915-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine

Intermediate 191A: 5-chloro-7-methylthiazolo[5,4-b]pyridin-2-amine

Potassium thiocyanate (0.682 g, 7.01 mmol) was dissolved in acetic acid(10 mL) and cooled to 0° C. 6-chloro-4-methylpyridin-3-amine (1.00 g,7.01 mmol) was dissolved in acetic acid (3.33 mL) and added dropwise.Bromine (0.361 mL, 7.01 mmol) was dissolved in acetic acid (3.33 mL) andadded dropwise to the reaction mixture. The reaction mixture was allowedto warm to room temperature for 18 h. The reaction mixture wasconcentrated under reduced pressure. The resultant residue was dilutedwith water and neutralized with 1 N NaOH. The aqueous solution wasextracted with EtOAc (×3). The combined organic layer was washed withbrine, dried with sodium sulfate, and concentrated under reducedpressure. The reaction mixture was purified on Prep HPLC using Method Ato yield Intermediate 191A (0.890 g, 4.46 mmol, 63.6% yield) as a whitesolid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.08 (d, J=0.7 Hz, 1H), 3.39(dt, J=3.2, 1.6 Hz, 2H), 2.50 (d, J=0.7 Hz, 3H). LC-MS: method H,RT=0.92 min, MS (ESI) m/z: 200.1 (M+H)⁺.

Intermediate 191B: 2-bromo-5-chloro-7-methylthiazolo[5,4-b]pyridine

Copper(II) bromide (0.295 g, 1.320 mmol) and t-butyl nitrite (0.157 mL,1.320 mmol) were dissolved in MeCN (3.11 mL) and allowed to stir 10minutes. Intermediate 191A (0.155 g, 0.776 mmol) was dissolved in MeCN(4.66 mL) and the copper solution was added. The reaction mixture wasstirred for 30 min. The reaction mixture was diluted with EtOAc, washedwith 1 N HCl, washed with saturated NaHCO₃, washed with brine, driedwith sodium sulfate, filtered, and concentrated in vacuo to yieldIntermediate 191B (0.163 g, 0.618 mmol, 80% yield). ¹H NMR (400 MHz,METHANOL-d₄) δ 7.43 (d, J=0.9 Hz, 1H), 2.68 (d, J=0.9 Hz, 3H). LC-MS:method H, RT=1.30 min, MS (ESI) m/z: 263.0 (M+H)⁺.

Example 191

Intermediate 191B (0.025 g, 0.095 mmol) was dissolved in Et₂O (0.379 mL)and cooled to −78° C. BuLi (0.042 mL, 0.104 mmol) was added and allowedto stir for 15 min. Tributylchlorostannane (0.026 mL, 0.095 mmol) wasadded and allowed to stir for 30 min. The reaction mixture was warmed toambient temperature and concentrated in vacuo. The crude material wassuspended in hexanes and filtered through dry celite. Used immediatelywithout further purification. Intermediate I-2E (0.015 g, 0.056 mmol),stannane, and potassium acetate (0.011 g, 0.112 mmol) were dissolved indioxane (0.562 mL) and degassed by bubbling with argon for 15 minutes.Pd(Ph₃P)₄ (3.24 mg, 2.81 μmol) was added and the reaction mixture wassealed and heated to 120° C. in the microwave for 2 hours. The reactionmixture was diluted with EtOAc and water. The layers were separated andthe organic layer was washed with brine, dried with sodium sulfate, andconcentrated under reduced pressure. The reaction mixture was dilutedwith DMF, filtered, and purified by preparative HPLC (Method D, 65% to100% B in 12 minutes) to yield Example 191 (0.0023 g, 6.08 μmol, 10.82%yield): ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.88 (s, 1H), 8.14 (s,1H), 7.62 (s, 1H), 4.84 (s, 2H), 3.49 (s, 3H), 2.84 (s, 3H), 2.73 (s,3H). LC-MS: method H, RT=1.11 min, MS (ESI) m/z: 371.2 (M+H)⁺.Analytical HPLC Method B: 98% purity.

Example 192(5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-7-yl)methanol

Intermediate 192A: 2-methoxy-5-nitroisonicotinic acid

2-chloro-5-nitroisonicotinic acid (0.100 g, 0.494 mmol) was dissolved inDCM (4.94 mL) and oxalyl chloride (0.043 mL, 0.494 mmol) was added. Tothe stirred reaction mixture was added 2 drops of DMF. The reactionmixture was stirred for 30 min and concentrated under reduced pressure.The compound was used without further purification in the next step. Theresidue was dissolved in tetrahydrofuran (4.98 mL) and sodium methoxide(3.98 mL, 1.991 mmol) was added. The reaction mixture was allowed tostir at room temperature for 18 h. The reaction mixture was diluted withwater and EtOAc. 1 N HCl was added and the layers were separated. Theorganic layer was washed brine, dried with sodium sulfate, andconcentrated under reduced pressure to yield Intermediate 192A (0.078 g,0.394 mmol, 79% yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d)δ 8.97 (s, 1H), 6.95 (s, 1H), 4.08 (s, 3H). LC-MS: method H, RT=0.82min, MS (ESI) m/z: 198.9 (M+H)⁺.

Intermediate 192B: methyl 2-methoxy-5-nitroisonicotinate

Intermediate 192A (0.085 g, 0.429 mmol) was dissolved in DCM (4.29 mL)and oxalyl chloride (0.038 mL, 0.429 mmol) was added. To the stirredreaction mixture was added 2 drops of DMF. The reaction mixture wasstirred for 30 min and concentrated under reduced pressure. The compoundwas used without further purification in the next step. The residuedissolved in MeOH (4.16 mL) and sodium methoxide (0.831 mL, 0.416 mmol)was added. The reaction mixture was stirred at room temperature for 18h. The reaction mixture was diluted with water and EtOAc. The layerswere separated and the organic layer was washed with water, brine, driedwith sodium sulfate, and concentrated under reduced pressure to yieldIntermediate 192B (0.060 g, 0.283 mmol, 68.1% yield) as a white solid.¹H NMR (400 MHz, CHLOROFORM-d) δ 8.96 (s, 1H), 6.86 (s, 1H), 4.06 (s,3H), 3.96 (s, 3H). LC-MS: method H, RT=0.83 min, MS (ESI) m/z: 213.1(M+H)⁺.

Intermediate 192C: methyl 5-amino-2-methoxyisonicotinate

Intermediate 192B (60 mg, 0.283 mmol) was dissolved in EtOH (1.131 mL).Pd/C (6.02 mg, 5.66 μmol) then ammonium formate (89 mg, 1.414 mmol) wereadded and the reaction mixture was heated to reflux for 1 h. Thereaction mixture was filtered through celite and concentrated in vacuoto yield Intermediate 192C (47.5 mg, 0.261 mmol, 92% yield): ¹H NMR (400MHz, CHLOROFORM-d) δ 7.80 (s, 1H), 7.15 (s, 1H), 5.09 (br. s., 2H), 3.91(s, 3H), 3.87 (s, 3H). LC-MS: method H, RT=0.67 min, MS (ESI) m/z: 183.1(M+H)⁺.

Intermediate 192D: methyl2-amino-5-methoxythiazolo[5,4-b]pyridine-7-carboxylate, 2 AcOH

Potassium thiocyanate (0.029 g, 0.299 mmol) was dissolved in acetic acid(10 mL) and cooled to 0° C. Intermediate 192C (0.0545 g, 0.299 mmol) wasdissolved in acetic acid (3.33 mL) and added dropwise. Bromine (0.015mL, 0.299 mmol) was dissolved in acetic acid (3.33 mL) and addeddropwise to the reaction mixture. The reaction mixture was allowed towarm to room temperature and stir for 18 h. The reaction mixture wasconcentrated under reduced pressure. The resultant residue was dilutedwith water and neutralized with 1 N NaOH. The aqueous solution wasextracted with EtOAc (×3). The combined organic layer was washed withbrine, dried with sodium sulfate, and concentrated under reducedpressure to yield Intermediate 192D (0.100 g, 0.278 mmol, 93% yield). ¹HNMR (400 MHz, METHANOL-d₄) δ 7.10 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H).LC-MS: method H, RT=0.67 min, MS (ESI) m/z: 240.1 (M+H)⁺.

Intermediate 192E: methyl2-bromo-5-methoxythiazolo[5,4-b]pyridine-7-carboxylate

Copper(II) bromide (0.106 g, 0.473 mmol) and t-butyl nitrite (0.056 mL,0.473 mmol) were dissolved in MeCN (1.113 mL) and allowed to stir 10minutes. Intermediate 192D (0.100 g, 0.278 mmol) was dissolved in MeCN(1.670 mL) and the copper solution was added. The reaction mixture wasstirred for 1 h. The reaction mixture was diluted with EtOAc, washedwith 1 N HCl, washed with saturated NaHCO₃, washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to yield Intermediate 192E(0.025 g, 0.082 mmol, 29.6% yield): ¹H NMR (400 MHz, CHLOROFORM-d) δ7.31 (s, 1H), 4.03 (s, 3H), 4.02 (s, 3H). LC-MS: method H, RT=0.96 min,MS (ESI) m/z: 303.0 (M+H)⁺.

Intermediate 192F:(2-bromo-5-methoxythiazolo[5,4-b]pyridin-7-yl)methanol

Intermediate 192E (25 mg, 0.082 mmol) was dissolved in toluene (550 μl)and THF (275 μl) and cooled to −78° C. 1 M DIBAL-H (181 μl, 0.181 mmol)was added, and the reaction mixture was allowed to stir for 18 h. Thereaction mixture was quenched with 1 N HCl (1 mL), diluted with EtOAc.The layers were separated and the organic layer was washed with brine,dried with sodium sulfate, and concentrated under reduced pressure toyield Intermediate 192F (0.02 g, 0.029 mmol, 35.3% yield). Used withoutfurther purification in the next step. LC-MS: method H, RT=0.96 min, MS(ESI) m/z: 275.0 (M+H)⁺.

Example 192

Intermediate I-2 (0.020 g, 0.064 mmol) and Intermediate 192E (0.018 g,0.064 mmol) were dissolved in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(3.12 mg, 3.82 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100mL, 0.300 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 25% to 55% B in 20 minutes) toyield Example 192 (0.0012 g, 3.01 μmol, 4.73% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 9.13 (s, 1H), 8.78 (d, J=1.9 Hz, 1H), 8.07 (s, 1H), 7.05 (s,1H), 5.64 (t, J=5.6 Hz, 1H), 5.13 (d, J=5.2 Hz, 2H), 4.83 (s, 2H), 4.01(s, 3H), 3.49 (s, 3H), 2.71 (s, 3H). LC-MS: method H, RT=1.02 min, MS(ESI) m/z: 383.1 (M+H)⁺. Analytical HPLC Method B: 98% purity.

Example 1934-fluoro-N-(2-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)benzenesulfonamide

Intermediate 193A: 2-amino-7-methylthiazolo[5,4-b]pyridin-5-ol,2hydrobromide

Intermediate I-16 (0.750 g, 3.84 mmol) was dissolved HBr in acetic acid(2.61 mL, 23.05 mmol) and the reaction mixture was stirred at 130° C.for 3h. The reaction mixture was concentrated under reduced pressure toyield Intermediate 193A (1.48 g, 4.31 mmol, 100%) as a tan solid. ¹H NMR(400 MHz, METHANOL-d₄) δ 6.66 (d, J=0.9 Hz, 1H), 2.48 (d, J=0.7 Hz, 3H)LC-MS: method H, RT=0.47 min, MS (ESI) m/z: 182.1 (M+H)⁺.

Intermediate 193B: tert-butyl(2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate

Intermediate 193A (0.100 g, 0.332 mmol) was dissolved in DMF (3.32 mL).t-Butyl (2-bromoethyl)carbamate (0.089 g, 0.398 mmol) and Cs₂CO₃ (0.541g, 1.659 mmol) were added and the reaction mixture was stirred at 40° C.for 3h. The reaction mixture was diluted with water and EtOAc. Thelayers were separated. The organic layer was washed with brine driedwith sodium sulfate, and concentrated under reduced pressure. Thereaction mixture was purified on ISCO using a 24 g column with a 0-100%gradient of EtOAc in hexanes to yield Intermediate 193B (0.038 g, 0.117mmol, 35.3% yield) a brown solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.53(s, 1H), 5.14 (br. s., 2H), 4.33 (t, J=5.2 Hz, 2H), 3.71 (t, J=5.0 Hz,1H), 3.52 (d, J=5.1 Hz, 2H), 2.49 (d, J=0.9 Hz, 3H). LC-MS: method H,RT=0.77 min, MS (ESI) m/z: 325.2 (M+H)⁺.

Intermediate 193C: tert-butyl(2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate

Copper(II) bromide (0.044 g, 0.199 mmol) and t-butyl nitrite (0.024 mL,0.199 mmol) were dissolved in MeCN (0.469 mL) and allowed to stir 10minutes. Intermediate 193B (0.038 g, 0.117 mmol) was dissolved in MeCN(0.703 mL) and the copper solution was added. The reaction mixture wasdiluted with EtOAc, washed with 1 N HCl, washed with saturated NaHCO₃,washed with brine, dried with sodium sulfate, filtered, and concentratedin vacuo to yield Intermediate 193C (0.042 g, 0.108 mmol, 92% yield).LC-MS: method H, RT=1.12 min, MS (ESI) m/z: 390.0 (M+H)⁺.

Intermediate 193D:2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethanamine

To a mixture of Intermediate 193C (0.042 g, 0.108 mmol) in DCM (1) wasadded 2,6-lutidine (0.038 mL, 0.325 mmol) followed by TMS-OTf (0.078 mL,0.433 mmol) at room temperature. The mixture was stirred at roomtemperature for 1 h. The mixture was diluted by EtOAc and NaHCO₃. Theorganic layer was washed by brine, dried by sodium sulfate andconcentrated to Intermediate 193D (0.0185 g, 0.064 mmol, 59.4% yield).¹H NMR (400 MHz, CHLOROFORM-d) δ 6.68 (d, J=0.9 Hz, 1H), 4.37 (t, J=5.3Hz, 2H), 3.11 (t, J=5.3 Hz, 2H), 2.63 (d, J=0.9 Hz, 3H), 2.53 (s, 1H).LC-MS: method H, RT=0.68 min, MS (ESI) m/z: 290.1 (M+H)⁺.

Intermediate 193E:N-(2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

To a solution of Intermediate 193D (0.018 g, 0.062 mmol) in DMF (1 mL)was added DIEA (0.109 mL, 0.625 mmol) and 4-fluorobenzene-1-sulfonylchloride (0.015 g, 0.075 mmol). The mixture was stirred at roomtemperature for 1 h. The reaction mixture was diluted with water andEtOAc. The layers were separated and the organic layer was washed withbrine, dried with sodium sulfate and concentrated under reduced pressureto yield Intermediate 193E (0.028 g, 0.063 mmol, 100% yield) as a yellowglass. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.89-7.84 (m, 2H), 7.15 (t,J=8.7 Hz, 2H), 6.55 (d, J=0.9 Hz, 1H), 4.97 (br. s., 1H), 4.43-4.32 (m,2H), 3.47-3.37 (m, 2H), 2.63 (d, J=0.9 Hz, 3H). LC-MS: method H, RT=1.09min, MS (ESI) m/z: 446.0 (M+H)⁺.

Example 193

Intermediate I-2 (0.010, 0.032 mmol) and Intermediate 193E (0.014 g,0.032 mmol) were dissolved in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(1.560 mg, 1.910 μmol) was added and the reaction mixture was degassedby bubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution(0.100 mL, 0.300 mmol) was added and the reaction mixture was degassedfor 5 minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was diluted with DMF, filtered, andpurified by preparative HPLC (Method D, 45% to 90% B in 20 minutes) toyield Example 193 (0.0053 g, 9.48 μmol, 29.8% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 9.09 (s, 1H), 8.76 (d, J=1.7 Hz, 1H), 8.03 (s, 1H), 7.92-7.88(m, 2H), 7.44-7.39 (m, 2H), 6.73 (s, 1H), 4.82 (s, 2H), 4.34 (t, J=5.5Hz, 2H), 3.49 (s, 3H), 3.26 (q, J=5.6 Hz, 2H), 2.73 (s, 3H), 2.69 (s,3H). LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 554.1 (M+H)⁺.Analytical HPLC Method B: 99% purity.

Example 1944-fluoro-N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)benzenesulfonamide

Intermediate I-2 (0.010, 0.032 mmol) and Example 193E (0.015 g, 0.032mmol) were dissolved in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct (1.560 mg,1.910 μmol) was added and the reaction mixture was degassed by bubblingwith argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100 mL, 0.300mmol) was added and the reaction mixture was degassed for 5 minutes,then sealed and heated to 90° C. in the microwave for 30 minutes. Thereaction mixture was diluted with DMF, filtered, and purified bypreparative HPLC (Method D, 60% to 90% B in 20 minutes) to yield Example194 (0.0043 g, 7.65 μmol, 23% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 8.72(s, 1H), 8.55 (d, J=1.4 Hz, 1H), 8.01 (t, J=5.8 Hz, 1H), 7.89 (dd,J=8.8, 5.2 Hz, 2H), 7.83 (s, 1H), 7.41 (t, J=8.8 Hz, 2H), 6.72 (s, 1H),4.33 (t, J=5.5 Hz, 2H), 4.09 (s, 3H), 3.26 (d, J=5.8 Hz, 2H), 2.72 (s,3H), 2.65 (s, 3H). LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 540.1(M+H)⁺. Analytical HPLC Method B: 96% purity.

Example 195 5-(benzofuran-2-yl)-2-(methoxymethyl)-7-methylquinoxaline

Intermediate 195A: ethyl5-(benzofuran-2-yl)-7-methylquinoxaline-2-carboxylate

Intermediate I-15 (0.250 g, 0.847 mmol) and benzofuran-2-ylboronic acid(0.137 g, 0.847 mmol) were dissolved in DMF (20 mL). PdCl₂(dppf)-CH₂Cl₂adduct (0.042 g, 0.051 mmol) was added and the reaction mixture wasdegassed by bubbling with argon for 15 minutes. Na₂CO₃ (3 mL, 6.00 mmol)was added and the reaction mixture was degassed for 5 minutes, thensealed and heated to 90° C. in the microwave for 30 minutes. Thereaction mixture was diluted with EtOAc and filtered through a micronfilter and concentrated in vacuo. Purified by ISCO to remove any Pd orligand based impurities. 40 g column with a 0-100% gradient of EtOAc inhexanes was used. Fractions pooled and the residue was purified on PrepHPLC using Method A to yield Intermediate 195A (0.074 g, 0.223 mmol,26.3% yield) LC-MS: method H, RT=1.19 min, MS (ESI) m/z: 333.0 (M+H)⁺.

Intermediate 195B: (5-(benzofuran-2-yl)-7-methylquinoxalin-2-yl)methanol

Intermediate 195A (0.010 g, 0.030 mmol) was dissolved in THF (1 mL).LiBH₄ (1.311 mg, 0.060 mmol) was added and the reaction mixture wasallowed to stir at room temperature for 18 h. The reaction mixture wasdiluted with water and EtOAc. The layers were separated and the organiclayer was washed with brine, dried with sodium sulfate, and concentratedunder reduced pressure to yield Intermediate 195B. LC-MS: method H,RT=1.07 min, MS (ESI) m/z: 291.1 (M+H)⁺. Used without furtherpurification in the next step.

Example 195

Intermediate 195B (0.0087 g, 0.030 mmol), Cs₂CO₃ (0.024 g, 0.075 mmol),and MeI (1.874 μl, 0.030 mmol) were dissolved in DMF (1 mL) and allowedto stir at 50° C. for over the weekend. The reaction mixture was dilutedwith water and EtOAc. The aqueous layer was back extracted with EtOAcand the combined organic layer was washed with brine, dried with sodiumsulfate, and concentrated under reduced pressure. The reaction mixturewas diluted with DMF, filtered, and purified by preparative HPLC (MethodD, 45% to 80% B in 20 minutes) to yield Example 195 (0.0006 g, 1.932μmol, 6.45% yield): ¹H NMR (500 MHz, METHANOL-d₄) δ 9.05 (s, 1H), 8.34(d, J=1.7 Hz, 1H), 8.15 (d, J=0.8 Hz, 1H), 7.80 (d, J=0.8 Hz, 1H), 7.68(d, J=7.4 Hz, 1H), 7.58-7.55 (m, 1H), 7.33 (td, J=7.7, 1.1 Hz, 1H),7.28-7.22 (m, 1H), 4.82 (s, 2H), 3.58 (s, 3H), 2.68 (s, 3H). LC-MS:method H, RT=1.17 min, MS (ESI) m/z: 305.3 (M+H)⁺. Analytical HPLCMethod B: 99% purity.

Example 1962-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethylpyridin-3-ylcarbamate

Intermediate 196A:2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate

Example 193A (0.050 g, 0.146 mmol) was dissolved in DMF. 2-Bromomethylacetate (0.058 g, 0.350 mmol) and Cs₂CO₃ (0.237 g, 0.729 mmol) wereadded and the reaction mixture was stirred at 40° C. for 18 h. Thereaction mixture was diluted with EtOAc and water. The layers wereseparated. The organic layer was washed with brine dried with sodiumsulfate, and concentrated under reduced pressure. The reaction mixturewas purified on ISCO using a 24 g column with a 0-100% EtOAc in hexanesgradient to yield Intermediate 196A (0.044 g, 0.165 mmol, 56.5% yield)as a pale yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.53-6.53 (m,1H), 5.01 (br. s., 2H), 4.52-4.48 (m, 2H), 4.44-4.39 (m, 2H), 2.49 (d,J=0.7 Hz, 3H), 2.09 (s, 3H). LC-MS: method H, RT=0.72 min, MS (ESI) m/z:268.2 (M+H)⁺.

Intermediate 196B:2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate

Copper(II) bromide (0.063 g, 0.280 mmol) and t-butyl nitrite (0.033 mL,0.280 mmol) were dissolved in MeCN (0.658 mL) and allowed to stir 10minutes. Intermediate 196A (0.044 g, 0.165 mmol) was dissolved in MeCN(0.988 mL) and the copper solution was added. The reaction mixture wasdiluted with EtOAc, washed with 1 N HCl, saturated NaHCO₃, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to yieldIntermediate 196B (0.046 g, 0.139 mmol, 84% yield): ¹H NMR (400 MHz,CHLOROFORM-d) δ 6.69 (d, J=0.9 Hz, 1H), 4.57-4.53 (m, 2H), 4.44-4.41 (m,2H), 2.63 (d, J=0.9 Hz, 3H), 2.09 (s, 3H). LC-MS: method H, RT=1.07 min,MS (ESI) m/z: 331.0 (M+H)⁺.

Intermediate 196C:2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethylacetate

Intermediate I-9 (0.042 g, 0.140 mmol) and Intermediate 196B (0.046 g,0.140 mmol) were dissolved in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(6.86 mg, 8.40 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100mL, 0.300 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was purified on ISCO using 24 g columnwith a 0-100% EtOAc in hexanes gradient to yield Intermediate 196C(0.021 g, 0.049 mmol, 35.4% yield) as an off white solid. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.60 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 7.75 (s, 1H),6.74 (s, 1H), 4.63 (dd, J=5.8, 3.6 Hz, 2H), 4.51-4.43 (m, 2H), 4.13 (s,3H), 2.79 (s, 3H), 2.66 (s, 3H), 2.11 (s, 3H). LC-MS: method H, RT=1.34min, MS (ESI) m/z: 425.1 (M+H)⁺.

Intermediate 196D:2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethanol

To a suspension of Intermediate 196C (0.143 g, 0.337 mmol) in THF (3 mL)and MeOH (1 mL) was added NaOH (1.011 mL, 1.011 mmol) at roomtemperature. The mixture was stirred at room temperature for 1 h. Themixture was diluted by EtOAc and 1N HCl, extracted by EtOAc, thecombined organic layer was washed by water and brine and dried by sodiumsulfate, and concentrated to yield Intermediate 196D (0.120 g, 0.314mmol, 93% yield) as a tan solid. ¹H NMR (400 MHz, METHANOL-d₄) δ 8.61(s, 1H), 8.58 (s, 1H), 7.78 (s, 1H), 6.82 (s, 1H), 4.48-4.45 (m, 2H),4.40-4.36 (m, 1H), 4.13 (s, 3H), 3.94-3.90 (m, 2H), 2.77 (s, 3H), 2.66(s, 3H). LC-MS: method H, RT=1.15 min, MS (ESI) m/z: 383.9 (M+H)⁺.

Intermediate 196E:2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethylcarbonochloridate

To a solution of Intermediate 196D (0.025 g, 0.065 mmol) in THF (3 mL)at room temperature was added 15% phosgene in toluene (0.231 mL, 0.327mmol) and the mixture was stirred at room temperature for 1 h. Thereaction mixture was concentrated under vacuum to give Intermediate 196E(0.030 g, 0.067 mmol, 100% yield) as an yellow solid. It was used forthe next step without any purification. LC-MS: method H, RT=1.35 min, MS(ESI) m/z: 444.7 (M+H)⁺.

Example 196

To a solution of Intermediate 196E (20 mg, 0.045 mmol) in DCM (1 mL) andTHF (0.5 mL) was added pyridin-3-amine (14.81 mg, 0.157 mmol) followedby DIEA (0.079 mL, 0.450 mmol). The mixture was stirred at roomtemperature for 1 h. The reaction mixture was diluted with EtOAc andwater. The combined organic layer was washed by brine and concentratedunder vacuum. The reaction mixture was diluted with DMSO, filtered, andpurified by preparative HPLC (Method D, 55% to 100% B in 20 minutes) toyield Example 196 (0.003 g, 5.61 μmol, 12.48% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 10.05 (br. s., 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.56 (d,J=1.4 Hz, 1H), 8.22 (d, J=4.7 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.84 (s,1H), 7.34 (dd, J=8.3, 4.7 Hz, 1H), 6.93 (s, 1H), 4.67-4.63 (m, 2H),4.55-4.48 (m, 2H), 4.09 (s, 3H), 2.75 (s, 3H), 2.65 (s, 3H). LC-MS:method H, RT=1.15 min, MS (ESI) m/z: 503.9 (M+H)⁺. Analytical HPLCMethod B: 94% purity.

Example 1972-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl(6-cyanopyridin-3-yl)carbamate

To a solution of Intermediate 196E (20 mg, 0.045 mmol) in DCM (1 mL) andTHF (0.5 mL) was added 5-aminopicolinonitrile (18.74 mg, 0.157 mmol)followed by DIEA (0.079 mL, 0.450 mmol). The mixture was stirred at roomtemperature for 0.5 h. The reaction mixture was allowed to stir for 18 hat 40° C. The reaction mixture was diluted with EtOAc and water. Thecombined organic layer was washed by brine and concentrated undervacuum. The reaction mixture was diluted with DMSO, filtered, andpurified by preparative HPLC (Method D, 50% to 85% B in 20 minutes) toyield Example 197 (3.2 mg, 5.88 μmol, 13% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 10.57 (s, 1H), 8.73 (d, J=2.2 Hz, 1H), 8.71 (s, 1H), 8.55 (s,1H), 8.11 (dd, J=8.7, 2.3 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.84 (s, 1H),6.92 (s, 1H), 4.71-4.66 (m, 2H), 4.58-4.53 (m, 2H), 4.09 (s, 3H), 2.74(s, 3H), 2.65 (s, 3H). LC-MS: method H, RT=1.24 min, MS (ESI) m/z: 527.8(M+H)⁺. Analytical HPLC Method B: 97% purity.

Example 1982-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl(6-cyanopyridin-3-yl)carbamate

Intermediate 198A: 2-amino-6-fluorothiazolo[5,4-b]pyridin-5-ol,2hydrobromide

Intermediate I-17 (0.500 g, 2.510 mmol) was dissolved HBr in acetic acid(1.704 mL, 15.06 mmol), and the reaction was stirred at 130° C. for 3 h.The reaction was concentrated under reduced pressure to yieldIntermediate 198A (0.422 g, 1.216 mmol, 48.5% yield) as a tan solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 7.67 (d, J=9.7 Hz, 1H). LC-MS: method H,RT=0.44 min, MS (ESI) m/z: 186.1 (M+H)⁺.

Intermediate 198B:2-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate

Intermediate 198A (0.100 g, 0.288 mmol) was dissolved in DMF (2.88 ml)and Cs₂CO₃ (0.376 g, 1.153 mmol) was added followed by 2-bromoethylacetate (0.058 g, 0.346 mmol). The reaction was stirred at roomtemperature for 3 h. Reaction was diluted with water and EtOAc. Thelayers were separated, and the aqueous layer was washed with EtOActhrice. The combined organic layer was washed with brine, dried withsodium sulfate, and concentrated under reduced pressure to yieldIntermediate 198B (0.079 g, 0.291 mmol, 101% yield) as a brown solid.Will be used without further purification in the next step. (0.079 g,0.291 mmol, 100% yield): ¹H NMR (400 MHz, CHLOROFORM-d₆) δ 7.46 (d,J=10.6 Hz, 1H), 4.65-4.54 (m, 2H), 4.49-4.43 (m, 2H), 2.10 (s, 4H).LC-MS: method H, RT=0.67 min, MS (ESI) m/z: 272.1 (M+H)⁺.

Intermediate 198C:2-((2-bromo-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate

Copper(II) bromide (0.078 g, 0.347 mmol) and t-butyl nitrite (0.041 ml,0.347 mmol) were dissolved in MeCN (0.818 ml) and allowed to stir for 10minutes. Intermediate 198B (0.080 g, 0.204 mmol) was dissolved in MeCN(1.226 ml), and the copper solution was added. The reaction was stirredfor 1 h. The reaction was diluted with EtOAc, washed with 1 N HCl,washed with saturated NaHCO₃, washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to yield Intermediate 198C (0.069 g,0.206 mmol, 100%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (d, J=9.7 Hz,1H), 4.69-4.65 (m, 2H), 4.51-4.46 (m, 2H), 2.10 (s, 3H). LC-MS: methodH, RT=0.96 min, MS (ESI) m/z: 335.0 (M+H)⁺.

Intermediate 198D:2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethylacetate

Intermediate I-9 (0.062 g, 0.206 mmol) and Intermediate 198C (0.069 g,0.206 mmol) were dissolved in DMF (1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(10.09 mg, 0.012 mmol) was added, and the reaction was degassed bybubbling with argon for 15 minutes. A 3 M aqueous solution of Na₂CO₃(0.100 ml, 0.300 mmol) was added, and the reaction was degassed for 5minutes. The reaction vessel was sealed and heated to 90° C. in themicrowave for 30 minutes. The reaction was filtered and purified on ISCOusing 24 g column with a 0-100% EtOAc in hexanes gradient to yieldIntermediate 198D (0.069 g, 0.161 mmol, 78% yield) as an off whitesolid. LC-MS: method H, RT=0.55 min, MS (ESI) m/z: 429.1 (M+H)⁺.

Intermediate 198E:2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethanol

To a suspension of Intermediate 198D (0.021 g, 0.049 mmol) in THF (1 mL)and MeOH (0.333 mL) was added NaOH (0.147 mL, 0.147 mmol) at roomtemperature. The mixture was stirred for 1 h. The mixture was dilutedwith EtOAc and 1N HCl. The layers were separated, and the aqueous layerwas back extracted with EtOAc. The combined organic layer was washedwith water, washed with brine, dried with Na₂SO₄, and concentrated underreduced pressure to yield Intermediate 198E (0.020 g, 0.052 mmol, 106%yield) as a white solid. Will be used without further purification inthe next step. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.58 (d, J=2.0 Hz, 1H),8.54 (s, 1H), 8.01 (d, J=10.1 Hz, 1H), 7.79-7.77 (m, 1H), 4.71-4.63 (m,2H), 4.13 (s, 3H), 4.08 (d, J=7.5 Hz, 2H), 2.65 (s, 3H). LC-MS: methodH, RT=1.09 min, MS (ESI) m/z: 387.1 (M+H)⁺.

Intermediate 198F:2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethylcarbonochloridate

To a solution of Intermediate 198E (0.025 g, 0.065 mmol) in THF (3 mL)at room temperature was added 15% phosgene in toluene (0.228 mL, 0.323mmol), and the mixture was stirred at room temperature for 2 h. Solventwas completely removed and the sample was under vacuum overnight toyield Intermediate 198F (0.029 g, 0.065 mmol, 100% yield) as a yellowsolid. LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 448.6 (M+H)⁺.

Example 198

To a solution of Intermediate 198F (15 mg, 0.033 mmol) in DCM (1 mL) andTHF (0.5 mL) was added 5-aminopicolinonitrile (13.93 mg, 0.117 mmol)followed by DIEA (0.058 mL, 0.334 mmol). The mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched with 0.2 mL ofMeOH. The reaction mixture was concentrated. The reaction mixture wasdiluted with DMSO, filtered, and purified by preparative HPLC (Method D,55% to 85% B in 20 minutes) to yield Example 198 (4.6 mg, 8.22 μmol,24.60% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 10.56 (br. s., 1H), 8.72 (d,J=8.8 Hz, 2H), 8.56 (br. s., 1H), 8.50 (d, J=11.3 Hz, 1H), 8.11 (d,J=8.0 Hz, 1H), 7.96-7.94 (m, 1H), 7.88 (br. s., 1H), 4.82 (br. s., 2H),4.61 (br. s., 2H), 4.10 (br. s., 3H), 2.65 (br. s., 3H). LC-MS: methodH, RT=1.16 min, MS (ESI) m/z: 532.1 (M+H)⁺. Analytical HPLC Method B:95% purity.

Example 199N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

In a vial charged with a stirring bar, Intermediate I-28 (130 mg, 0.406mmol) and Intermediate I-5 (235 mg, 0.527 mmol) were dissolved in1,4-dioxane (8 mL). Na₂CO₃ (6 mL, 12.00 mmol) was added, followed byPdCl₂(dppf)-CH₂Cl₂ adduct (16.56 mg, 0.020 mmol). The mixture wasstirred at 100° C. for 1 hour. After cooling to room temperature, thereaction mixture was diluted by adding 30 mL of EtOAc and 20 mL ofwater. After separation, the aqueous layer was extracted with 20 mL ofEtOAc. Then organic phases were combined, washed with brine, dried overNa₂SO₄ and concentrated. The crude product was purified by flashchromatography (40 g silica gel column, 0-100% EtOAc/Hexane) to giveExample 199 as a yellow solid (203 mg, 90%). ¹H NMR (500 MHz, DMSO-d₆) δ8.75 (s, 1H), 8.59 (d, J=2.2 Hz, 1H), 8.03 (br s, 1H), 7.99 (d, J=2.2Hz, 1H), 7.90 (dd, J=8.8, 5.2 Hz, 2H), 7.48-7.39 (m, 3H), 6.85 (d, J=1.4Hz, 1H), 4.07 (s, 3H), 4.04 (s, 2H), 3.22 (br s, 2H), 2.70 (s, 3H);LC-MS: method J, RT=1.27 min, MS (ESI) m/z: 559.1 (M+H)⁺.

Examples 200 to 225

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 199 and theexamples above.

LCMS LCMS Ex. [M + H]⁺ RT (Min)/ No. Structure m/z Method NMR 200

573.2  1.15/J ¹H NMR (500 MHz, chloroform-d) δ 9.14 (s, 1H), 9.01 (d, J= 2.5 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.97- 7.90 (m, 2H), 7.20 (t, J= 8.5 Hz, 2H), 7.16 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 4.98(t, J = 6.3 Hz, 1H), 4.86 (s, 2H), 4.11 (t, J = 5.2 Hz, 2H), 3.60 (s,3H), 3.45 (d, J = 5.5 Hz, 2H), 2.83 (s, 3H). 201

386.1  1.29/H ¹H NMR (500 MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.84 (s, 1H),8.32 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.77 (br s, 1H), 7.19 (d, J =8.8 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H). 202

372.10 2.19/L ¹H NMR (500 MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.84 (s, 1H),8.32 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.77 (br s, 1H), 7.19 (d, J =8.8 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H). 203

436.15 2.882/L ¹H NMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.82 (br s,1H), 8.20 (br s, 1H), 7.59 (br s, 1H), 7.04 (br s, 1H), 4.86 (s, 2H),3.87 (d, J = 1.1 Hz, 3H), 3.50 (s, 3H), 2.76 (s, 3H). 204

410.2  2.434/L ¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (d, J = 1.9 Hz, 1H),9.26 (s, 1H), 8.68 (d, J = 1.9 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.03(s, 1H), 4.86 (s, 2H), 4.02 (s, 3H), 3.86 (s, 3H), 3.50 (s, 3H), 2.76(s, 3H). 205

597.15 2.323/L ¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (d, J = 1.7 Hz, 1H),9.23 (s, 1H), 8.65 (d, J = 1.9 Hz, 1H), 8.04 (br s, 1H), 7.94-7.85 (m,2H), 7.50-7.38 (m, 3H), 6.88 (s, 1H), 4.85 (s, 2H), 4.06 (t, J = 5.1 Hz,2H), 4.02 (s, 3H), 3.49 (s, 3H), 3.23 (t, J = 5.0 Hz, 2H), 2.74 (s, 3H).206

370.2  1.23/J ¹H NMR (400 MHz, chloroform-d) δ 9.12 (s, 1H), 8.85 (dd, J= 9.9, 2.9 Hz, 1H), 7.78 (dd, J = 8.6, 2.9 Hz, 1H), 6.96 (d, J = 1.3 Hz,1H), 4.86 (s, 2H), 3.91 (s, 3H), 3.60 (s, 3H), 2.83 (s, 3H). 207

557.2  1.12/J ¹H NMR (400 MHz, chloroform-d) δ 9.12 (s, 1H), 8.85 (dd, J= 9.7, 2.9 Hz, 1H), 7.99-7.88 (m, 2H), 7.79 (dd, J = 8.4, 2.9 Hz, 1H),7.24-7.15 (m, 3H), 6.86 (s, 1H), 4.99 (t, J = 5.8 Hz, 1H), 4.86 (s, 2H),4.11 (t, J = 5.0 Hz, 2H), 3.60 (s, 3H), 3.45 (q, J = 5.5 Hz, 2H),2.85-2.79 (m, 3H). 208

420.05 2.74/L ¹H NMR (500 MHz, METHANOL-d₄) δ 9.22 (s, 1H), 9.13 (d, J =1.5 Hz, 1H), 8.39 (s, 1H), 7.27 (d, J = 2.5 Hz, 1H), 6.92 (s, 1H), 4.86(s, 2H), 3.88 (s, 3H), 3.59 (s, 3H), 2.78 (s, 3H). 209

629.05 (M + Na)⁺ 2.625/L ¹H NMR (500 MHz, METHANOL-d₄) δ 9.23 (s, 1H),9.13 (d, J = 1.5 Hz, 1H), 8.40 (s, 1H), 7.94-7.87 (m, 2H), 7.26-7.09 (m,3H), 6.82 (s, 1H), 4.87 (s, 2H), 4.06 (t, J = 5.4 Hz, 2H), 3.59 (s, 3H),3.35 (t, J = 5.4 Hz, 2H), 2.77 (s, 3H). 210

406.1  1.23/H ¹H NMR (400 MHz, chloroform-d) δ 9.14 (s, 1H), 9.08 (d, J= 2.4 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.21(d, J = 2.4 Hz, 1H), 4.86 (s, 2H), 3.93 (s, 3H), 3.60 (s, 3H). 211

363.0  2.633/L ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (br s, 1H), 8.94 (s,1H), 8.54 (br s, 1H), 7.58 (br s, 1H), 7.05 (br s, 1H), 4.14 (br s, 3H),3.87 (br s, 3H), 2.78 (br s, 3H). 212

372.0  1.06/J ¹H NMR (400 MHz, chloroform-d) δ 9.17 (s, 1H), 9.14 (dd, J= 7.5, 1.3 Hz, 1H), 8.20 (dd, J = 8.1, 1.3 Hz, 1H), 7.95 (t, J = 7.9 Hz,1H), 7.35 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 4.88 (s, 2H),3.93 (s, 3H), 3.60 (s, 3H). 213

539.20 2.542/L ¹H NMR (500 MHz, DMSO-d₆) δ 9.16 (br s, 1H), 9.01-8.94(m, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.06 (br s, 2H), 7.90 (br s, 2H),7.49-7.38 (m, 3H), 6.86 (br s, 1H), 4.83 (br s, 2H), 4.05 (br s, 2H),3.47 (br s, 3H), 3.22 (br s, 2H), 2.73 (br s, 3H). 214

393.6  1.23/J ¹H NMR (400 MHz, chloroform-d) δ 8.86 (d, J = 2.2 Hz, 1H),8.59 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 6.7, 1.9 Hz, 1H),4.15 (s, 3H), 4.02 (s, 3H); ¹⁹F NMR (376 MHz, chloroform-d) δ −146.29(d, J = 18.3 Hz, 1F), −160.18 (dd, J = 18.3, 6.9 Hz, 1F). 215

410.0  1.45/J ¹H NMR (400 MHz, Dioxane) δ 8.85 (d, J = 2.4 Hz, 1H), 8.63(s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 4.11 (s,3H), 3.97 (s, 3H); ¹⁹F NMR (376 MHz, dioxane) δ −136.60 (s, 1F). 216

404.05 2.289/L ¹H NMR (500 MHz, DMSO-d₆) δ 8.47 (s, 1H), 8.03 (d, J =7.4 Hz, 1H), 7.90 (s, 1H), 4.05 (s, 3H), 3.98 (s, 3H), 2.54 (s, 3H),2.29 (s, 3H). 217

385.10 2.341/K ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.99 (s, 1H),8.59 (s, 1H), 6.86 (d, J = 7.7 Hz, 1H), 3.99 (s, 3H), 3.25 (br s, 3H).218

406.05 2.049/L ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (br s, 2H), 8.01-7.89(m, 2H), 5.66 (br s, 1H), 4.83 (br s, 2H), 4.09 (br s, 3H), 3.97 (br s,3H). 219

382.15 2.228/L ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (br s, 2H), 7.91 (br s,1H), 7.55 (br s, 1H), 5.63 (d, J = 3.9 Hz, 1H), 4.85 (br s, 2H), 4.11(br s, 3H), 3.91 (br s, 3H), 2.76 (br s, 3H), 2.26 (br s, 3H). 220

390.15 1.957/L ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (br s, 2H), 7.90 (br s,1H), 7.76 (br s, 1H), 5.66 (br s, 1H), 4.83 (br s, 2H), 4.10 (br s, 3H),3.98 (br s, 3H). 221

367.10 2.234/L ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.88 (d, J =1.9 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.05-7.98 (m, 2H), 4.13 (s, 3H),3.97 (s, 3H). 222

372.10 1.851/L ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.73 (d, J =1.7 Hz, 1H), 8.01-7.88 (m, 3H), 5.62 (t, J = 5.8 Hz, 1H), 4.82 (d, J =5.8 Hz, 2H), 4.09 (s, 3H), 3.96 (s, 3H). 223

369.15 2.010/L ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.68 (s, 1H),7.91 (s, 1H), 6.87 (s, 1H), 5.62 (t, J = 5.8 Hz, 1H), 4.82 (d, J = 5.5Hz, 2H), 4.09 (s, 3H), 3.95 (s, 3H), 2.72 (s, 3H). 224

424.15 2.106/L ¹H NMR (500 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.61 (s, 1H),6.21 (s, 1H), 4.87 (d, J = 5.8 Hz, 2H), 4.12 (s, 3H), 3.98 (s, 3H).

Example 2258-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-carboxamide

Intermediate 225A:8-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-carboxylicacid

Example 205 (223 mg, 0.374 mmol) was dissolved in THF (10 mL) and water(10 mL). The mixture was treated with LiOH.H2O (31.4 mg, 0.748 mmol) at40° C. for 1 hour. After cooling to room temperature, the reactionmixture was diluted by adding 30 mL of EtOAc and 10 ml of water,followed by 2 mL of 1N HCl (aq.). After shaking and separation, theorganic phase was washed with 10 mL of brine and dried over Na₂SO₄.Concentration gave the desired product as a white solid (145 mg, 63.9%).¹H NMR (500 MHz, DMSO-d₆) δ 9.40 (s, 1H), 9.21 (s, 1H), 8.63 (s, 1H),8.04 (t, J=5.4 Hz, 1H), 7.90 (dd, 5.4 Hz, 2H), 7.51-7.35 (m, 3H), 6.86(s, 1H), 4.85 (s, 2H), 4.05 (t, J=5.0 Hz, 2H), 3.48 (br s, 3H), 3.22 (d,J=5.0 Hz, 2H), 2.74 (s, 3H); LC-MS: method L, RT=1.939 min, MS (ESI)m/z: 583.15 (M+H)⁺.

Example 225

Intermediate 225A (30 mg, 0.051 mmol) was dissolved in DMF (1 mL). NH₄Cl(8.26 mg, 0.154 mmol) was added, followed by HATU (23.49 mg, 0.062 mmol)and DIEA (0.027 mL, 0.154 mmol). The mixture was stirred at roomtemperature for 3 h. LCMS showed starting material remained. Another 3equivalents of DIEA and NH₄Cl and 1 equivalents of HATU were added. Thereaction mixture was stirred at room temperature for an additional 2 h.The crude material was purified via preparative LC with condition D anddried via centrifugal evaporation to yield the desired product (5.5 mg,0.0095 mmol, 18.4%). ¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (d, J=1.4 Hz, 1H),9.22 (s, 1H), 8.74 (d, J=1.7 Hz, 1H), 8.50 (br s, 1H), 8.02 (br s, 1H),7.90 (dd, J=8.5, 5.2 Hz, 2H), 7.82 (br s, 1H), 7.47 (s, 1H), 7.43 (t,J=8.8 Hz, 2H), 6.88 (s, 1H), 4.86 (s, 2H), 4.06 (t, J=5.2 Hz, 2H), 3.49(s, 3H), 3.27-3.16 (m, 2H), 2.76 (s, 3H); LC-MS: method L, RT=1.80 min,MS (ESI) m/z: 582.15 (M+H)⁺.

Examples 226 to 228

The following additional examples were prepared, isolated andcharacterized using the methods described above for Example 225.

Example 2268-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)-N,N-dimethylquinoxaline-6-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (d, J=1.4 Hz, 1H), 9.22 (s, 1H), 8.74(d, J=1.7 Hz, 1H), 8.50 (br s, 1H), 8.02 (br s, 1H), 7.90 (dd, 5.2 Hz,2H), 7.82 (br s, 1H), 7.47 (s, 1H), 7.43 (t, J=8.8 Hz, 2H), 6.88 (s,1H), 4.86 (s, 2H), 4.06 (t, J=5.2 Hz, 2H), 3.49 (s, 3H), 3.27-3.16 (m,2H), 2.76 (s, 3H); LC-MS: method L, RT=1.80 min, MS (ESI) m/z: 582.15(M+H)⁺.

Example 2274-fluoro-N-(2-((2-(2-(methoxymethyl)-7-(piperidine-1-carbonyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.88 (d, J=1.4 Hz, 1H), 8.16(d, J=1.4 Hz, 1H), 8.03 (br s, 1H), 7.90 (dd, 5.2 Hz, 2H), 7.47 (s, 1H),7.43 (t, J=8.8 Hz, 2H), 6.87 (s, 1H), 4.84 (s, 2H), 4.10-4.02 (m, 2H),3.71 (br s, 2H), 3.48 (s, 3H), 3.42 (br s, 2H), 3.22 (br s, 2H), 2.72(br s, 3H), 1.66 (br s, 4H), 1.54 (br s, 2H); LC-MS: method L, RT=2.27min, MS (ESI) m/z: 650.25 (M+H)⁺.

Example 2288-(6-(2-(4-fluorophenylsulfonamido)ethoxy)-4-methylbenzo[d]thiazol-2-yl)-N-(2-methoxyethyl)-3-(methoxymethyl)quinoxaline-6-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (d, J=1.7 Hz, 1H), 9.22 (s, 1H), 9.08(br s, 1H), 8.71 (d, J=1.7 Hz, 1H), 8.03 (br s, 1H), 7.93-7.87 (m, 2H),7.48 (s, 1H), 7.42 (t, J=8.8 Hz, 2H), 6.88 (s, 1H), 4.86 (s, 2H), 4.06(t, J=5.0 Hz, 2H), 3.55 (br s, 5H), 3.49 (s, 3H), 3.31 (s, 2H),3.26-3.19 (m, 2H), 2.76 (s, 3H); LC-MS: method L, RT=1.92 min, MS (ESI)m/z: 640.20 (M+H)⁺.

Example 2294-fluoro-N-(2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

To a vial charged with a stirring bar was added Example 199 (20 mg,0.036 mmol), potassium vinyl trifluoroborate (9.58 mg, 0.072 mmol),Cs₂CO₃ (35.0 mg, 0.107 mmol), (S)-BINAP (4.46 mg, 7.16 μmol) and PdOAc₂(0.803 mg, 3.58 μmol). DMF (1 mL) was added. After degassing withbubbling N₂ for 10 minutes, the vial was sealed and was heated at 120°C. for 1 hour. After cooling to room temperature, the reaction mixturewas diluted by adding 10 mL of EtOAc and 10 mL of water. Afterseparation, the organic phase was passed through anhydrous Na₂SO₄ andconcentrated on a rotary evaporator. The crude material was purified viapreparative LC/MS (method C) and dried via centrifugal evaporation toyield the Example 229 (1.9 mg, 0.0034 mmol, 9.6%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.82 (d, J=1.7 Hz, 1H), 8.74 (s, 1H), 8.05 (d, J=1.7 Hz, 1H),8.03 (br s, 1H), 7.97-7.83 (m, 2H), 7.49-7.38 (m, 3H), 7.08 (dd, J=17.6,11.0 Hz, 1H), 6.86 (d, J=1.4 Hz, 1H), 6.19 (d, J=17.9 Hz, 1H), 5.57 (d,J=11.0 Hz, 1H), 4.09 (s, 3H), 4.05 (t, J=5.4 Hz, 2H), 3.22 (br s, 2H),2.74 (s, 3H);); LC-MS: method K, RT=2.59 min, MS (ESI) m/z: 559.1(M+H)⁺.

Example 230N-(2-((2-(7-ethynyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Intermediate 230A:4-fluoro-N-(2-((2-(2-methoxy-7-((trimethylsilyl)ethynyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

In a microwave vial charged with a stirring bar, a solution of Example199 (20 mg, 0.036 mmol), PdCl₂(CH₃CN)₂(1.856 mg, 7.16 mol),2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (6.82 mg, 0.014mmol) and Cs₂CO₃ (29.1 mg, 0.089 mmol) in acetonitrile (1 mL)) wasstirred for 0.5 h at room temperature under N₂ atmosphere. To themixture was added ethynyltrimethylsilane (35.1 mg, 0.358 mmol), and theresultant mixture was stirred for 1 hour at 90° C. in the microwave. Thereaction mixture was concentrated under reduced pressure, and theresulting residue was purified by flash chromatography (24 g silica gelcolumn, 0-50% EtOAc/Hexane gradient) to give Intermediate 230A as ayellow solid (13.6 mg, 61.2%). LC-MS: method B, RT=3.0 min, MS (ESI)m/z: 621.1 (M+H)⁺.

Example 230

Intermediate 230A (10 mg, 0.016 mmol) was dissolved in MeOH (0.5 mL)/DCM(0.5 mL) and was treated with K₂CO₃ (1.113 mg, 8.05 μmol) for 1 hour.The solid was filtered and solvent was removed on a rotary evaporator.The crude material was purified via preparative LC/MS (method C) anddried via centrifugal evaporation to yield the title compound (1.4 mg,0.0025 mmol, 16%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.70 (d,J=1.7 Hz, 1H), 8.02 (d, J=1.7 Hz, 2H), 7.90 (dd, 5.4 Hz, 2H), 7.47-7.38(m, 3H), 6.86 (s, 1H), 4.58 (s, 1H), 4.09 (s, 3H), 4.05 (t, J=5.2 Hz,2H), 3.22 (d, J=5.2 Hz, 2H), 2.72 (s, 3H); LC-MS: method L, RT=2.58 min,MS (ESI) m/z: 549.15 (M+H)⁺.

Example 231N-(2-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Example 199 (40 mg, 0.072 mmol), Pd₂(dba)₃ (19.66 mg, 0.021 mmol), DPPF(23.80 mg, 0.043 mmol), dicyanozinc (8.40 mg, 0.072 mmol) and zinc (7.02mg, 0.107 mmol) were mixed in NMP (1 mL) in a microwave vial that wasflushed with N₂ for 10 minutes. The resulting mixture was heated at 120°C. with vigorous stirring until LCMS showed the disappearance ofstarting material (3 h). The mixture was cooled to room temperature,diluted with ethyl acetate (50 ml), and then washed with water andbrine. After drying over Na₂SO₄, the ethyl acetate solution wasconcentrated by rotary evaporation. The crude material was purified viapreparative LC/MS-HPLC, method D and dried via centrifugal evaporationto give Example 231 (7.4 mg, 0.013 mmol, 18.8%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.92 (s, 1H), 8.87 (d, J=1.7 Hz, 1H), 8.48 (d, J=1.7 Hz, 1H),7.90 (dd, J=8.5, 5.5 Hz, 3H), 7.45-7.39 (m, 3H), 6.87 (s, 1H), 4.11 (s,3H), 4.05 (t, J=5.1 Hz, 2H), 3.22 (t, J=5.2 Hz, 2H), 2.72 (s, 3H);LC-MS: method L, RT=2.205 min, MS (ESI) m/z: 550.10 (M+H)⁺.

Examples 232 and 233

Examples 232 and 233 were prepared, isolated and characterized using themethods described in Example 231 above.

Example 232N-(2-((2-(7-cyano-2-(methoxymethyl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Example 232 was made from Example 200. ¹H NMR (500 MHz, DMSO-d₆) δ 9.24(s, 1H), 9.02 (d, J=1.7 Hz, 1H), 8.77 (d, J=1.7 Hz, 1H), 7.90 (dd,J=8.8, 5.2 Hz, 3H), 7.44 (d, J=9.1 Hz, 2H), 6.86 (d, J=1.1 Hz, 1H), 4.84(s, 2H), 4.05 (t, J=5.2 Hz, 2H), 3.49 (s, 3H), 3.23 (t, J=5.1 Hz, 2H),2.72 (s, 3H); LC-MS: method L, RT=2.074 min, MS (ESI) m/z: 564.15(M+H)⁺.

Example 2338-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-(methoxymethyl)quinoxaline-6-carbonitrile

Example 233 was made from Example 201. ¹H NMR (400 MHz, chloroform-d) δ9.28 (s, 1H), 9.25 (d, J=2.0 Hz, 1H), 8.48 (d, J=1.8 Hz, 1H), 7.28-7.27(m, 1H), 6.99 (dd, J=2.6, 0.9 Hz, 1H), 4.90 (s, 2H), 3.93 (s, 3H), 3.63(s, 3H), 2.04 (s, 3H); LC-MS: method J, RT=1.08 min, MS (ESI) m/z: 377.1(M+H)⁺.

Example 2344-fluoro-N-(2-((2-(2-(methoxymethyl)-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

To a vial charged with a stirring bar was added Example 200 (40 mg,0.070 mmol), potassium vinyl trifluoroborate (18.70 mg, 0.140 mmol),Cs₂CO₃ (68.2 mg, 0.209 mmol), (S)-BINAP (17.39 mg, 0.028 mmol) andPdOAc₂ (3.13 mg, 0.014 mmol). DMF (1 mL) was added. After degassing withbubbling N₂ for 10 minutes, the vial was sealed and was heated at 120°C. for 1 hour. After cooling to room temperature, the reaction mixturewas diluted by adding 10 mL of EtOAc and 10 mL of water. Afterseparation, the organic phase was passed through Na₂SO₄ and concentratedon a rotary evaporator. The crude material was purified via preparativeLC/MS with condition D and dried via centrifugal evaporation to yieldExample 234 (10.6 mg, 0.018 mmol, 25.5%). ¹H NMR (500 MHz, DMSO-d₆) δ9.09 (s, 1H), 9.04 (d, J=1.7 Hz, 1H), 8.26 (d, J=1.4 Hz, 1H), 8.04 (brs, 1H), 7.90 (dd, 5.2 Hz, 2H), 7.48-7.39 (m, 3H), 7.13 (dd, J=17.6, 11.0Hz, 1H), 6.86 (s, 1H), 6.23 (d, J=17.3 Hz, 1H), 5.62 (d, J=11.0 Hz, 1H),4.81 (s, 2H), 4.06 (t, J=5.1 Hz, 2H), 3.47 (s, 3H), 3.22 (t, J=5.2 Hz,2H), 2.75 (s, 3H); LC-MS: method L, RT=2.203 min, MS (ESI) m/z: 565.15(M+H)⁺.

Example 2354-fluoro-N-(2-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Intermediate 235A:4-fluoro-N-(2-((2-(7-formyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Sodium periodate (0.424 g, 1.983 mmol) was added to a solution ofExample 229 (0.364 g, 0.661 mmol) and osmium(VIII) oxide (0.084 mL,0.013 mmol) in THF (10 mL) and water (3 mL). After 6 h, 20 mL of waterand 30 mL of EtOAc was added. Phases were separated, and the aqueousphase was extracted with ethyl acetate (20 mL) and then the combinedorganic phases were washed with sodium thiosulfate solution and brine,dried over sodium sulfate, filtered and concentrated to giveIntermediate 235A (0.319 g, 0.576 mmol, 87.2% yield) as a yellow solid.LC-MS: method J, RT=1.30 min, MS (ESI) m/z: 553.1 (M+H)⁺.

Example 235

Intermediate 235A (16 mg, 0.029 mmol) was dissolved in 1,4-dioxane (1mL)/MeOH (1 mL) and was treated with NaBH₄ (2.191 mg, 0.058 mmol) atroom temperature for 30 minutes. Several drops of saturated NH₄Cl (aq.)were added to quench the reaction. The reaction mixture was diluted byadding 15 mL of EtOAc and 10 mL of water. After separation, the organicphase was washed with brine, dried over Na₂SO₄, filtered, and solventwas removed to give crude product. The crude material was purified viapreparative LC/MS with the condition C and dried via centrifugalevaporation to yield Example 235 (6.3 mg, 0.011 mmol, 39%). ¹H NMR (500MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.73 (s, 1H), 8.03 (t, J=5.8 Hz, 1H),7.94-7.87 (m, 3H), 7.46-7.39 (m, 3H), 6.86 (s, 1H), 5.61 (t, J=5.8 Hz,1H), 4.83 (d, J=5.5 Hz, 2H), 4.09 (s, 3H), 4.05 (t, J=5.4 Hz, 2H), 3.22(q, J=5.4 Hz, 2H), 2.73 (s, 3H); LC-MS: method L, RT=2.046 min, MS (ESI)m/z: 555.15 (M+H)⁺.

Example 236N-(2-((2-(7-(1,2-dihydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Example 229 (7 mg, 0.013 mmol) was suspended in acetone (1 mL)/water(0.3 mL). 4-Methylmorpholine N-oxide (1.787 mg, 0.015 mmol) was added,followed by OsO₄ (1.616 μl, 0.254 μmol). The mixture was stirred at roomtemperature overnight. On the next day, solvent was removed on a rotaryevaporator and the residue was dissolved in 5 mL of EtOAc and was washedwith 5 mL of water, dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude material was purified via preparative LC/MSwith the condition D and dried via centrifugal evaporation to affordExample 236 (3.9 mg, 0.0064 mmol, 50%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.78(d, J=1.9 Hz, 1H), 8.76 (s, 1H), 8.03 (br s, 1H), 7.93 (d, J=1.7 Hz,1H), 7.92-7.87 (m, 2H), 7.46-7.39 (m, 3H), 6.86 (d, J=1.7 Hz, 1H), 5.68(d, J=3.3 Hz, 1H), 4.87 (br s, 2H), 4.09 (s, 3H), 4.05 (t, J=5.2 Hz,2H), 3.69-3.56 (m, 2H), 3.22 (t, J=5.2 Hz, 2H), 2.73 (s, 3H); LC-MS:method L, RT=1.833 min, MS (ESI) m/z: 585.20 (M+H)⁺.

Example 2374-fluoro-N-(2-((2-(7-(2-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

To a solution of Example 229 (20 mg, 0.036 mmol) in THF (1 mL) under N₂at 0° C. was added BH₃.THF (0.036 mL, 0.036 mmol) slowly. The reactionmixture was allowed to warm to room temperature and stir at roomtemperature for 3 h. The reaction mixture was cooled in an ice bath, andNaOH (2.91 mg, 0.073 mmol) in EtOH/H₂O (2:1, 0.6 mL) was added, followedby H₂O₂ (0.011 mL, 0.109 mmol) dropwise. The mixture was warmed to roomtemperature and stirred at room temperature for 18 h. On the next day, asmall amount of saturated NH₄Cl (aq.) was added to quench the reaction.The reaction mixture was diluted by adding 15 mL EtOAc and 10 mL ofwater. After separation, the aqueous layer was passed through anhydrousNa₂SO₄ and solvent was removed on a rotary evaporator. The crude productwas purified by prep-HPLC with method B and dried on a lyophilizer togive Example 237 (1.32 mg, 0.002 mmol, 5.9%). ¹H NMR (400 MHz, DMSO-d₆)δ 8.76 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.04 (br s, 1H), 7.95-7.86 (m,3H), 7.48-7.40 (m, 3H), 6.87 (d, J=1.5 Hz, 1H), 4.77 (t, J=5.3 Hz, 1H),4.10 (s, 3H), 4.06 (t, J=5.3 Hz, 2H), 3.85-3.78 (m, 2H), 3.23 (br s,2H), 3.07 (t, J=6.6 Hz, 2H), 2.74 (s, 3H); LC-MS: method J, RT=0.83 min,MS (ESI) m/z: 569.1 (M+H)⁺.

Example 238N-(2-((2-(7-(aminomethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Intermediate 238A:N-(2-((2-(7-(((2,4-dimethoxybenzyl)amino)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Intermediate 235A (110 mg, 0.199 mmol) was dissolved in THF (2 mL) andmixed with (2,4-dimethoxy phenyl) methanamine (133 mg, 0.796 mmol).Acetic acid (0.114 mL, 1.991 mmol) was added and the reaction mixturewas stirred at room temperature for 30 minutes. SodiumTriacetoxyborohydride (93 mg, 0.438 mmol) was added. The mixture wasstirred at room temperature for 6 h. The reaction mixture was diluted byadding 30 mL of EtOAc and was washed with saturated NaHCO₃(aq.) andbrine, and concentrated on a rotary evaporator to give crude productthat was purified by flash chromatography (24 g, 30-100% EtOAc/Hexane in20 minutes) to give the title compound (79 mg, 0.092 mmol, 46.2% yield)as a yellow solid. ¹H NMR (400 MHz, chloroform-d) δ 8.78 (s, 1H), 8.59(s, 1H), 7.99 (s, 1H), 7.93 (dd, J=8.1, 5.1 Hz, 2H), 7.23-7.17 (m, 3H),7.15 (s, 1H), 6.82 (s, 1H), 6.49-6.44 (m, 2H), 4.96 (br s, 1H), 4.14 (s,3H), 4.12-4.05 (m, 5H), 3.87-3.83 (m, 5H), 3.82 (s, 3H), 3.44 (br s,2H), 2.83 (s, 3H); LC-MS: method H, RT=1.13 min, MS (ESI) m/z: 704.2(M+H)⁺.

Example 238

Intermediate 238A (76 mg, 0.108 mmol) was dissolved in DCM (1 mL) andwas treated with TFA (1 ml, 12.98 mmol) at room temperature for 18 h. Noproduct was shown on LCMS. Then mixture was transferred to a microwavevial and was irradiated at 100° C. for 2 h. Then solvent was removed ona rotary evaporator, residue was dissolved in small amount of DCM/MeOHand evaporated. The crude product was purified on prep-HPLC condition Dand dried via centrifugal evaporation to afford Example 238 (24 mg,0.043 mmol, 40%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (d, J=9.9 Hz, 1H),7.99 (s, 1H), 7.96-7.86 (m, 2H), 7.48-7.38 (m, 3H), 6.86 (br s, 1H),4.09 (br s, 3H), 4.06 (d, J=4.4 Hz, 2H), 3.36-3.29 (m, 2H), 3.23 (d,J=4.4 Hz, 2H), 2.74 (s, 2H), 2.52 (br s, 3H); LC-MS: method L, RT=1.617min, MS (ESI) m/z: 554.20 (M+H)⁺.

Example 2394-fluoro-N-(2-((2-(7-(1-hydroxyethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Intermediate 235A (15 mg, 0.027 mmol) was dissolved in THF (2 mL) andwas treated with CH₃MgBr in ether (0.018 mL, 0.054 mmol) at −78° C.After addition, the mixture was warmed to room temperature slowly, and asmall amount of NH₄Cl (sat., aq.) was added to quench the reaction. 10mL of EtOAc and 5 mL of water was added to dilute the reaction mixture.After separation, the organic phase was passed through Na₂SO₄ andsolvent was removed on a rotary evaporator. The crude material waspurified via preparative LC/MS and dried via centrifugal evaporation toyield Example 239 (1.6 mg, 0.0027 mmol, 10%). ¹H NMR (500 MHz, DMSO-d₆)δ 8.78 (d, J=1.9 Hz, 1H), 8.76 (s, 1H), 8.03 (br s, 1H), 7.94-7.87 (m,3H), 7.46-7.41 (m, 3H), 6.86 (d, J=1.7 Hz, 1H), 5.58 (d, J=4.1 Hz, 1H),5.09-5.02 (m, 1H), 4.09 (s, 3H), 4.05 (t, J=5.4 Hz, 2H), 3.22 (t, J=5.4Hz, 2H), 2.73 (s, 3H), 1.49 (d, J=6.6 Hz, 3H); LC-MS: method K, RT=2.119min, MS (ESI) m/z: 569.2 (M+H)⁺.

Example 2404-fluoro-N-(2-((2-(7-(hydroxy(phenyl)methyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Example 240 was made by following the procedure of Example 239. ¹H NMR(500 MHz, chloroform-d) δ 8.83 (d, J=1.9 Hz, 1H), 8.58 (s, 1H), 7.99 (d,J=1.4 Hz, 1H), 7.94-7.89 (m, 2H), 7.51 (d, J=7.4 Hz, 2H), 7.41-7.35 (m,2H), 7.31 (d, J=7.4 Hz, 1H), 7.19 (t, J=8.5 Hz, 2H), 7.12 (d, J=2.2 Hz,1H), 6.81 (d, J=1.7 Hz, 1H), 6.14 (d, J=3.3 Hz, 1H), 4.97 (s, 1H), 4.12(s, 3H), 4.08 (t, J=5.1 Hz, 2H), 3.46-3.40 (m, 2H), 2.79 (s, 3H), 2.51(d, J=3.6 Hz, 1H); LC-MS: method L, RT=2.380 min, MS (ESI) m/z: 631.2(M+H)⁺.

Example 2414-fluoro-N-(2-((2-(2-methoxy-7-(prop-1-en-2-yl)quinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Example 199 (42.5 mg, 0.076 mmol) was dissolved in 1,4-dioxane (1.5 mL)and mixed with4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (25.6 mg,0.152 mmol). Na₂CO₃ (1 mL, 2.000 mmol) was added, followed byPdCl₂(dppf)-CH₂Cl₂ adduct (6.21 mg, 7.60 μmol). The mixture was stirredin a microwave at 120° C. for 1 hour. After it cooled to roomtemperature, the reaction mixture was diluted by adding 15 mL of EtOAcand 10 mL of water. After separation, the organic phase was washed withbrine and dried over Na₂SO₄. Removing solvent on a rotary evaporatorgave crude product that was purified by flash chromatography (4 g silicacolumn, 0-50% EtOAc/Hexane gradient) to give Example 241 (22 mg, 0.035mmol, 46.6% yield) as a yellow solid. ¹H NMR (400 MHz, chloroform-d) δ8.98 (d, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.00-7.90 (m, 3H), 7.24-7.16 (m,2H), 7.13 (d, J=2.2 Hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 5.75 (s, 1H), 5.36(s, 1H), 5.03 (t, J=6.1 Hz, 1H), 4.15 (s, 3H), 4.09 (t, J=5.0 Hz, 2H),3.44 (q, J=5.5 Hz, 2H), 2.82 (s, 3H), 2.35 (s, 3H); LC-MS: method H,RT=1.17 min, MS (ESI) m/z: 565.1 (M+H)⁺.

Example 2424-fluoro-N-(2-((2-(7-(2-hydroxypropan-2-yl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Intermediate 242A:N-(2-((2-(7-acetyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)-4-fluorobenzenesulfonamide

Sodium periodate (22.73 mg, 0.106 mmol) was added into a solution ofExample 241 (20 mg, 0.035 mmol), Osmium tetroxide (5.56 μl, 0.708 μmol)in THF (1 ml) and water (0.3 mL), and stirred for 6 h. 10 mL of waterand 20 mL of EtOAc was added. After separation, the aqueous layer wasextracted with ethyl acetate (10 mL) and then the combined organicphases were washed with sodium thiosulfate solution and brine, driedover sodium sulfate, filtered and concentrated to give Intermediate 242A(20.07 mg, 0.035 mmol, 100% yield) as product. LC-MS: method H, RT=1.14min, MS (ESI) m/z: 566.8 (M+H)⁺.

Example 242

Intermediate 242A (20 mg, 0.035 mmol) was dissolved in THF (2 mL) underN₂ and was cooled to −78° C. CH₃MgBr (0.047 mL, 0.141 mmol) was addedinto the reaction mixture slowly. The mixture was warmed to roomtemperature slowly, and a small amount of NH₄Cl (saturated aq.) wasadded to quench the reaction. The reaction mixture was diluted by adding10 mL of EtOAc and 10 mL of water. After separation, the organic phasewas concentrated, purified via preparative LC/MS with condition D, anddried via centrifugal evaporation to yield Example 242 (2.4 mg, 0.0038mmol, 11%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (d, J=1.9 Hz, 1H), 8.76 (s,1H), 8.06 (br s, 1H), 8.00 (d, J=1.9 Hz, 1H), 7.90 (dd, J=8.8, 5.2 Hz,2H), 7.45-7.40 (m, 3H), 6.85 (d, J=1.7 Hz, 1H), 5.51 (s, 1H), 4.09 (s,3H), 4.04 (t, J=5.4 Hz, 2H), 3.21 (t, J=5.1 Hz, 2H), 2.73 (s, 3H), 1.60(s, 6H); LC-MS: method L, RT=2.183 min, MS (ESI) m/z: 583.2 (M+H)⁺.

Example 243(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol

Intermediate 243A:5-fluoro-6-methoxy-2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazole

Intermediate 243A was made by following the procedure in Example 234.LC-MS: method J, RT=1.05 min, MS (ESI) m/z: 382.1 (M+H)⁺.

Intermediate 243B:8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carbaldehyde

Intermediate 243B was made by following the procedure in Intermediate235A. LC-MS: method J, RT=0.86 min, MS (ESI) m/z: 384.1 (M+H)⁺.

Example 243

Example 243 was made by following the procedure in Example 235. ¹H NMR(500 MHz, chloroform-d) δ 8.81 (s, 1H), 8.60 (s, 1H), 7.97 (s, 1H), 7.30(d, J=7.7 Hz, 1H), 5.02 (d, J=3.0 Hz, 2H), 4.14 (s, 3H), 3.99 (s, 3H),2.78 (s, 3H), 2.01 (br s, 1H); LC-MS: method L, RT=2.059 min, MS (ESI)m/z: 386.15 (M+H)⁺.

Examples 244 to 246

Examples 244 to 246 were made by following the general proceduredescribed in Example 239.

Example 2441-(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)ethanol

¹H NMR (500 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.76 (s, 1H), 7.93 (s, 1H),7.76 (d, J=7.7 Hz, 1H), 5.61 (br s, 1H), 5.06 (br s, 1H), 4.09 (s, 3H),3.93 (s, 3H), 2.69 (br s, 3H), 1.49 (d, J=5.8 Hz, 3H); LC-MS: method L,RT=2.234 min, MS (ESI) m/z: 400.15 (M+H)⁺.

Example 245(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)(phenyl)methanol

¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.73 (s, 1H), 7.94 (s, 1H),7.73 (d, J=8.0 Hz, 1H), 7.51 (d, J=7.4 Hz, 2H), 7.36 (t, J=7.4 Hz, 2H),7.28-7.22 (m, 1H), 6.35 (br s, 1H), 6.06 (br s, 1H), 4.07 (s, 3H), 3.92(s, 3H), 2.66 (s, 3H); LC-MS: method L, RT=2.428 min, MS (ESI) m/z:462.20 (M+H)⁺.

Example 246Cyclopropyl(8-(5-fluoro-6-methoxy-4-methylbenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol

¹H NMR (500 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.77 (s, 1H), 7.97 (s, 1H),7.77 (d, J=8.0 Hz, 1H), 5.62 (br s, 1H), 4.31 (br s, 1H), 4.09 (s, 3H),3.94 (s, 3H), 2.69 (br s, 3H), 1.28-1.11 (m, 1H), 0.59-0.43 (m, 4H);LC-MS: method L, RT=2.324 min, MS (ESI) m/z: 426.15 (M+H)⁺.

Example 2474-fluoro-N-(2-((2-(7-fluoro-2-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Example 247 was a side product isolated from the synthesis of Example207. ¹H NMR (400 MHz, chloroform-d) δ 8.86 (s, 1H), 8.80 (dd, J=9.8, 3.0Hz, 1H), 7.99-7.90 (m, 2H), 7.73 (dd, J=8.5, 3.0 Hz, 1H), 7.21 (t, J=8.6Hz, 2H), 7.16 (d, J=2.4 Hz, 1H), 6.85 (s, 1H), 5.03-4.96 (m, 1H), 4.11(t, J=5.0 Hz, 2H), 3.45 (q, J=5.6 Hz, 2H), 2.84 (s, 3H), 2.82 (s, 3H);LC-MS: method J, RT=1.15 min, MS (ESI) m/z: 527.1 (M+H)⁺.

Example 248(8-(5-fluoro-6-isopropoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxalin-6-yl)methanol

Example 248 was prepared from Intermediate I-35 by following theprocedure described in Example 199. ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s,1H), 8.67 (s, 1H), 7.92 (d, J=3.7 Hz, 1H), 7.90 (s, 1H), 7.87 (s, 1H),4.80 (d, J=5.8 Hz, 2H), 4.72 (dt, J=12.1, 6.0 Hz, 1H), 4.06 (s, 3H),1.35 (d, J=6.1 Hz, 6H); LC-MS: method L, RT=2.16 min, MS (ESI) m/z:399.95 (M+H)⁺.

Example 249N-(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)pyridine-3-sulfonamide

Intermediate 249A: tert-butyl(2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl)carbamate

Intermediate 249A was made from Intermediate I-28 and Intermediate I-5Dby following the procedure described in Example 199. LC-MS: method J,RT=1.28 min, MS (ESI) m/z: 501.1 (M+H)⁺.

Intermediate 249B:2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanamine,TFA Salt

Intermediate 249A (237 mg, 0.473 mmol) was dissolved in DCM (2 mL) andwas treated with TFA (1 mL, 12.98 mmol) at room temperature for 1 hour.After 1 hour, the solvent was removed on a rotary evaporator and theresidue coevaporated with DCM (3×). The residue was dried in vacuo andthe crude product was used in the next step without furtherpurification. LC-MS: method H, RT=1.04 min, MS (ESI) m/z: 400.7 (M+H)⁺.

Example 249

Intermediate 249B (20 mg, 0.050 mmol) was suspended in DCM (4 mL).Pyridine-3-sulfonyl chloride hydrochloride (16.02 mg, 0.075 mmol) wasadded, followed by DIEA (0.035 mL, 0.200 mmol) and the mixture wasstirred at room temperature for 30 minutes. Solvent was removed and thecrude material was purified via preparative LC/MS with condition C toyield Example 249 (3.5 mg, 0.0064, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ9.00 (d, J=1.9 Hz, 1H), 8.81 (dd, J=4.8, 1.2 Hz, 1H), 8.77 (s, 1H), 8.61(d, J=2.2 Hz, 1H), 8.26 (t, J=5.8 Hz, 1H), 8.22 (dt, J=8.3, 1.8 Hz, 1H),8.01 (d, J=2.5 Hz, 1H), 7.63 (dd, J=7.8, 4.8 Hz, 1H), 7.41 (d, J=2.5 Hz,1H), 6.82 (d, J=1.4 Hz, 1H), 4.08 (s, 3H), 4.06 (t, J=5.2 Hz, 2H), 3.29(m, 2H), 2.70 (s, 3H); LC-MS: method L, RT=2.554 min, MS (ESI) m/z:542.15 (M+H)⁺.

Example 250 Ethyl2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)acetate

Example 250 was prepared from Intermediate I-28 and Intermediate I-39 byfollowing the procedure described in Example 199. ¹H NMR (400 MHz,chloroform-d) δ 8.81 (d, J=2.4 Hz, 1H), 8.60 (s, 1H), 7.93 (d, J=2.4 Hz,1H), 7.23 (d, J=2.2 Hz, 1H), 7.01 (dd, J=2.4, 0.9 Hz, 1H), 4.71 (s, 2H),4.31 (q, J=7.3 Hz, 2H), 4.14 (s, 3H), 2.84 (s, 3H), 1.33 (t, J=7.2 Hz,3H); LC-MS: method L, RT=2.834 min, MS (ESI) m/z: 444.10 (M+H)⁺.

Example 2512-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)aceticacid

Example 251 was another product isolated during purification of 250. ¹HNMR (500 MHz, chloroform-d) δ 8.81 (d, J=2.2 Hz, 1H), 8.60 (s, 1H), 7.94(d, J=1.9 Hz, 1H), 7.27 (s, 1H), 7.02 (s, 1H), 4.77 (s, 2H), 4.14 (s,3H), 2.85 (s, 3H); LC-MS: method L, RT=2.398 min, MS (ESI) m/z: 416.05(M+H)⁺.

Example 2522-((2-(7-(hydroxymethyl)-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl(6-methoxypyridin-3-yl)carbamate

Intermediate 252A:2-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol

Example 250 (230 mg, 0.518 mmol) was dissolved in 1,4-dioxane (5 mL) andwas cooled to 0° C. under N₂. The mixture was treated with LiBH₄ (16.93mg, 0.777 mmol) at room temperature for 18 h. On the next morning, asmall amount of saturated NH₄Cl (aq.) was added to quench the reaction.The reaction mixture was diluted by adding 50 mL of EtOAc and 20 mL ofwater. After shaking and separation, 30 mL of EtOAc was used to extractthe aqueous phase. The combined organic phases were dried over Na₂SO₄,filtered, and concentrated to give Intermediate 252A, which was usedwithout purification. LC-MS: method H, RT=0.93 min, MS (ESI) m/z: 402.1(M+H)⁺.

Intermediate 252B:2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethanol

Intermediate 252B was prepared from Intermediate 252A by followingprocedure described in Example 229. LC-MS: method J, RT=0.81 min, MS(ESI) m/z: 394.1 (M+H)⁺.

Intermediate 252C:2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethylcarbonochloridate

Phosgene in toluene (0.922 mL, 1.398 mmol) was added dropwise toIntermediate 252B (110 mg, 0.280 mmol) dissolved in anhydrous THF (10mL). The mixture was stirred at room temperature for 4 hours. Solventwas removed by rotary evaporator and the residue was used in the nextstep without purification. LC-MS: method J, RT=1.10 min, MS (ESI) m/z:456.1 (M+H)⁺.

Intermediate 252D:2-((2-(2-methoxy-7-vinylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl(6-methoxypyridin-3-yl)carbamate

Intermediate 252C (30 mg, 0.066 mmol) was mixed with DIEA (0.046 mL,0.263 mmol) in DCM (1 mL) and 6-methoxypyridin-3-amine (24.51 mg, 0.197mmol) was added. The mixture was stirred at room temperature for 18hours. On the next day, the reaction mixture was purified by flashchromatography (12 g silica column, 0-100% EtOAc/Hexane gradient), andthe product was purified again by preparative HPLC with method B anddried on a lyophilizer to give Intermediate 252D (5.6 mg, 10.30 μmol,15.66% yield) as a yellow solid. LC-MS: method H, RT=1.21 min, MS (ESI)m/z: 544.1 (M+H)⁺.

Intermediate 252E:2-((2-(7-formyl-2-methoxyquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-yl)oxy)ethyl(6-methoxypyridin-3-yl)carbamate

Intermediate 252E was prepared from Intermediate 252D by following theprocedure described in Intermediate 235A. LC-MS: method H, RT=1.11 min,MS (ESI) m/z: 545.8 (M+H)⁺.

Example 252

Example 252 was prepared from Intermediate 252E by following theprocedure described in Example 235. ¹H NMR (500 MHz, DMSO-d₆) δ 9.77 (brs, 1H), 8.75 (s, 1H), 8.72 (d, J=1.7 Hz, 1H), 8.24 (br s, 1H), 7.91 (d,J=0.8 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.03 (d,J=1.7 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 5.61 (t, J=5.8 Hz, 1H), 4.83 (d,J=5.8 Hz, 2H), 4.54-4.41 (m, 2H), 4.40-4.27 (m, 2H), 4.09 (s, 3H), 3.80(s, 3H), 2.75 (s, 3H); LC-MS: method L, RT=1.955 min, MS (ESI) m/z:548.2 (M+H)⁺.

Example 2536-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 253A: 2-bromo-6-methoxybenzo[d]thiazole

To a black solution of Copper (II) bromide (149 mg, 0.666 mmol) inAcetonitrile (1 mL) was added t-Butyl nitrite (0.095 mL, 0.721 mmol) atroom temperature followed by 6-methoxybenzo[d]thiazol-2-amine (100 mg,0.555 mmol). Immediate bubbling and a mild exotherm was observed uponbenzothiazole addition. After 3 hours, the reaction mixture was dilutedwith EtOAc and washed with 1.0 M HCl, saturated NaHCO₃, and then Brine.The organic phase was dried over MgSO₄, filtered and concentrated to areddish-brown solid. The crude material was purified by ISCO flashchromatography (0-15% EtOAc/Hex over 20 min, 12 g silica gel cartridge,Product at 5%). The desired fractions were combined and concentrated toyield Intermediate 253A (84 mg, 0.344 mmol, 62.0% yield) as an off-whitesolid. LC-MS: Method H, RT=1.12 min, MS (ESI) m/z: 244.0, 246.0 (M+H)⁺.¹H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (d, J=9.0 Hz, 1H), 7.28 (1H underCDCl3), 7.09 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s, 3H)

Example 253

Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 253A (15.78 mg,0.065 mmol) were solvated in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct (2.82mg, 3.45 μmol) was added and the solution was degassed by sparging withargon for 10 min. Sodium carbonate (9.14 mg, 0.086 mmol) was then added,followed by water (0.100 mL), and the solution was further degassed foran additional 5 min. The vial was sealed and heated to 100° C. in themicrowave for 30 min. The crude solution was filtered and purified bypreparative HPLC (Method D, 40-80% over 20 minutes) to yield Example 253(6.7 mg, 0.019 mmol, 43.8% yield). LC-MS: Method H, RT=1.31 min, MS(ESI) m/z: 353.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (d, J=9.0Hz, 1H), 7.28 (1H Under CDCl₃), 7.09 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s,3H).

Example 2544-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 254A: 4-fluoro-6-methoxybenzo[d]thiazol-2-amine

To a solution of 2-fluoro-4-methoxyaniline (150 mg, 1.063 mmol) inAcetonitrile (5.314 mL) was added ammonium thiocyanate (121 mg, 1.594mmol). The mixture was stirred at room temperature for 5 min until fullysolvated. Benzyltrimethylammonium tribromide (414 mg, 1.063 mmol) wasthen added at room temperature causing the solution to take on a brightyellow color with solids precipitating. The mixture was allowed to stirat room temperature overnight, at which point LCMS indicated completeconversion. The mixture was diluted with EtOAc and washed with saturatedsodium bicarbonate. The organic layer was collected, washed with brine,dried over magnesium sulfate, filtered and concentrated. The crudematerial was purified by ISCO (0-10% DCM/MeOH over 20 min using a 24 gsilica gel cartridge) to give Intermediate 254A (101 mg, 0.510 mmol,47.9% yield). LC-MS: Method H, RT=0.77 min, MS (ESI) m/z: 199.1 (M+H)⁺.¹H NMR (400 MHz, METHANOL-d₄) δ 7.01 (d, J=2.0 Hz, 1H), 6.67 (dd,J=12.4, 2.3 Hz, 1H), 3.78 (s, 3H), 3.33-3.28 (m, 2H).

Intermediate 254B: 4-fluoro-6-methoxybenzo[d]thiazol-2-amine

To a dark green solution of Copper (II) bromide (125 mg, 0.560 mmol) andIntermediate 254A (101 mg, 0.510 mmol) solvated in acetonitrile (1 mL)and THF (2 mL) was added t-butyl nitrite (0.088 mL, 0.662 mmol). Afterstirring for 4 h at room temperature, the mixture was dilute with EtOAcand washed with 1.0 M HCl followed by Brine. The organic phase wasconcentrated and purified by ISCO flash chromatography (0-10% EtOAc/Hexover 20 min, 24 g silica gel cartridge-product at 5%) to affordIntermediate 254B (63 mg, 0.240 mmol, 47.2% yield) as a white solid.LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 262.0, 264.0 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.05 (dd, J=2.2, 0.9 Hz, 1H), 6.83 (dd,J=11.6, 2.3 Hz, 1H), 3.87 (s, 3H).

Example 254

Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 254B (14.68 mg,0.056 mmol) were solvated in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct (2.82mg, 3.45 μmol) was added and the solution was degassed by bubbling argonfor 10 min. Sodium Carbonate (2.0 M in H₂O) (100 μL, 0.200 mmol) wasthen added, and the solution was further degassed for an additional 5min. The microwave vial was sealed and heated to 100° C. in themicrowave for 30 min. The crude reaction mixture was diluted with Et₂Oand washed with water followed by brine. The organic phase wasconcentrated and purified by ISCO (24 g, 0-50% EtOAc/Hex, 18min—recovered SM at 10%, Product at 20%). Example 254 (2.2 mg, 5.78μmol, 13.40% yield) was isolated as a bright yellow solid. LC-MS: MethodH, RT=1.37 min, MS (ESI) m/z: 370.1 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 9.09 (s, 1H), 8.94 (s, 1H), 7.97 (s, 1H), 7.29-7.21 (m,2H under CDCl₃), 6.88 (dd, J=11.8, 2.3 Hz, 1H), 4.86 (s, 2H), 3.93 (s,3H), 3.59 (s, 3H), 2.71 (s, 3H).

Example 2556-ethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 255A: 2-bromo-6-ethoxybenzo[d]thiazole

To a solution of Copper (II) bromide (138 mg, 0.618 mmol) inacetonitrile (1 mL) was added t-butyl nitrite (0.088 mL, 0.669 mmol) atroom temperature followed by 6-ethoxybenzo[d]thiazol-2-amine (100 mg,0.515 mmol). The reaction mixture was heated to 50° C. for 45 min. Themixture was cooled to room temperature, diluted with EtOAc and washedwith 1.0 M HCl followed by brine. The organic phase was dried overMgSO₄, filtered and concentrated. The crude material was purified byISCO (24 g, 0-15% EtOAc/Hex). Example 255A (62 mg, 0.240 mmol, 46.7%yield) was isolated as a light brown solid. LC-MS: Method H, RT=1.19min, MS (ESI) m/z: 258.2, 260.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.86 (d, J=9.0 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 7.06 (dd, J=8.9, 2.3 Hz,1H), 4.09 (q, J=7.0 Hz, 2H), 1.46 (t, J=6.9 Hz, 3H).

Example 255

Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 255A (16.69 mg,0.065 mmol) were solvated in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct (2.82mg, 3.45 μmol) was added and the solution was degassed by bubbling argonfor 10 min. Sodium Carbonate (2.0 M in H₂O) (100 μL, 0.200 mmol) wasthen added, and the solution was further degassed for an additional 5min. The vial was sealed and heated to 100° C. in the microwave for 30min in the microwave. The crude solution was filtered and purified bypreparative HPLC (Method D, 50-90% over 10 minutes) to yield Example 255(5.4 mg, 0.015 mmol, 34.3% yield). LC-MS: Method H, RT=1.38 min, MS(ESI) m/z: 366.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.89 (d, J=9.0Hz, 1H), 7.28 (1H Under CDCl₃), 7.09 (dd, J=9.0, 2.6 Hz, 1H), 3.90 (s,3H).

Example 2562-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 256A: 2-bromo-6-ethoxybenzo[d]thiazole

To a solution of copper (II) bromide (134 mg, 0.600 mmol) inAcetonitrile (1 mL) was added benzo[d]thiazol-2-amine (100 mg, 0.666mmol) at room temperature. t-Butyl nitrite (0.106 mL, 0.800 mmol) wasthen added. Bubbling immediately observed. After 30 min, diluted withEtOAc and washed with 1.0 M HCl followed by brine. The organic phase wasconcentrated and purified by ISCO flash chromatography (0-5% EtOAc/Hexover 20 min, 24 g silica gel cartridge—product at 2.5%) to affordIntermediate 256A (80 mg, 0.374 mmol, 56.1% yield) as a pink oil. LC-MS:Method H, RT=1.16 min, MS (ESI) m/z: 214.0, 216.0 (M+H)⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.00 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H),7.53-7.37 (m, 2H).

Example 256

Intermediate I-2 (19.2 mg, 0.061 mmol) and Intermediate 256A (10.0 mg,0.047 mmol) were solvated in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂ adduct (3.05mg, 3.74 μmol) was added and the solution was degassed by bubbling argonfor 10 min. Sodium Carbonate (2.0 M in H₂O) (100 μL, 0.200 mmol) wasthen added, and the solution was further degassed for an additional 5min. The vial was sealed and heated to 100° C. in the microwave for 30min. The crude solution was filtered and purified by preparative HPLC(Method D, 45-90% over 10 minutes) to yield 256 (3.2 mg, 0.008 mmol,34.3% yield). LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 322.0 (M+H)⁺.¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.87 (s, 1H), 8.21 (d, J=8.0Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.58 (t, J=7.7 Hz, 1H),7.52-7.46 (m, 1H), 4.82 (s, 2H), 3.47 (s, 3H), 2.70 (s, 3H).

Example 2574,6-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 257A: 2-bromo-4,6-difluorobenzo[d]thiazole

To a black solution of copper (II) bromide (144 mg, 0.645 mmol) inAcetonitrile (1 mL) was added t-Butyl nitrite (0.092 mL, 0.698 mmol)followed by 4,6-difluorobenzo[d]thiazol-2-amine (100 mg, 0.537 mmol).The reaction mixture was heated to 50° C. After 40 min, the reactionmixture was cooled to room temperature, diluted with EtOAc and washedwith 1.0 M HCl followed by brine. The crude material was concentratedand purified by flash chromatography (0-15% EtOAc/Hex over 18 min, 12 gsilica gel cartridge). The desired fractions were combined andconcentrated to yield Intermediate 257A (126 mg, 0.504 mmol, 94% yield)as a white solid. LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: None(M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.35 (d, J=7.5 Hz, 1H), 7.03(td, J=9.6, 2.2 Hz, 1H). ¹⁹F NMR (CHLOROFORM-d) δ −85.7, −91.7

Example 257

Intermediate I-2 (15.1 mg, 0.048 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (2.61mg, 3.20 μmol) and Intermediate 257A (10 mg, 0.040 mmol) were solvatedin DMF (1 mL). Sodium carbonate (2.0 M in H₂O) (100 μL, 0.200 mmol) wasadded, and the solution was degassed with argon for 10 min. The vial wasthen sealed and heated to 100° C. in the microwave for 30 min. The crudesolution was filtered and purified by preparative HPLC (Method D, 45-85%over 10 minutes) to yield Example 257 (8.3 mg, 0.021 mmol, 52.3% yield).LC-MS: Method H, RT=1.41 min, MS (ESI) m/z: 358.0 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.84 (s, 1H), 8.09 (s, 1H), 8.03-7.97 (m,1H), 7.51 (t, J=9.4 Hz, 1H), 4.82 (s, 2H), 3.47 (s, 3H), 2.70 (s, 3H).

Example 2584,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 258A: 2-bromo-4,6-dimethoxybenzo[d]thiazole

To a solution of copper (II) bromide (127 mg, 0.571 mmol) inacetonitrile (1 mL) was added 4,6-dimethoxybenzo[d]thiazol-2-amine (100mg, 0.476 mmol) at room temperature. t-Butyl nitrite (0.082 mL, 0.618mmol) was then added dropwise at room temperature causing immediatebubbling. After 1 hr, the reaction mixture was diluted with EtOAc andwashed with 1.0 M HCl. The organic phase was dried over MgSO₄, filteredand concentrated. The crude material was purified by ISCO flashchromatography (0-30% EtOAc/Hex over 35 min, 12 g silica gel cartridge).Intermediate 258A (56 mg, 0.204 mmol, 43% yield) as a white solid.LC-MS: Method H, RT=1.13 min, MS (ESI) m/z: 274.0, 276.0 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 6.81 (d, J=2.0 Hz, 1H), 6.52 (d, J=2.2 Hz,1H), 3.99 (s, 3H), 3.86 (s, 3H).

Example 258

Intermediate I-2 (13.8 mg, 0.044 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (2.38mg, 2.92 μmol) and Intermediate 258A (10 mg, 0.036 mmol) were solvatedin DMF (1 mL). Sodium carbonate (2.0 M in H₂O) (100 μL, 0.200 mmol) wasadded, and the solution was degassed with argon for 10 min. The vial wasthen sealed and heated to 100° C. in the microwave for 30 min. The crudesolution was filtered and purified by preparative HPLC (Method D, 45-85%over 10 minutes) to yield Example 258 (6.4 mg, 0.015 mmol, 41.9% yield).LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 382.0 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.77 (s, 1H), 8.02 (s, 1H), 7.29 (s, 1H),6.68 (s, 1H), 4.81 (s, 2H), 4.00 (s, 3H), 3.87 (s, 3H), 3.47 (s, 3H),2.69 (s, 3H).

Example 2594-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 259A: 2-bromo-4-methoxybenzo[d]thiazole

Copper (II) bromide (112 mg, 0.499 mmol) and4-methoxybenzo[d]thiazol-2-amine (100 mg, 0.555 mmol) were solvated inAcetonitrile (1 mL) t-Butyl nitrite (0.081 mL, 0.610 mmol) was added atroom temperature. After 30 min, the reaction mixture was dilute withEtOAc and washed with 1.0 M HCl followed by brine. The crude materialwas concentrated and purified by ISCO flash chromatography (0-10%EtOAc/Hex over 20 min, 24 g silica gel cartridge) to afford Intermediate259A (68 mg, 0.279 mmol, 50.2% yield). LC-MS: Method H, RT=1.12 min, MS(ESI) m/z: 242.0. 244.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.39-7.36 (m, 2H), 6.92 (dd, J=6.2, 2.9 Hz, 1H), 4.05 (s, 3H).

Example 259

Intermediate I-2 (15.4 mg, 0.049 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (2.68mg, 3.28 μmol) and Intermediate 259A (10 mg, 0.041 mmol) were solvatedin DMF (1 mL). Sodium Carbonate (2.0 M in H₂O) (100 μL, 0.200 mmol) wasadded, and the solution was degassed with argon for 10 min. The vial wasthen sealed and heated to 100° C. in the microwave for 30 min. The crudesolution was filtered and purified by preparative HPLC (Method D, 45-85%over 10 minutes) to yield Example 259 (4.1 mg, 0.012 mmol, 28.5% yield).LC-MS: Method H, RT=1.30 min, MS (ESI) m/z: 352.1 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.84 (s, 1H), 8.06 (s, 1H), 7.73 (d, J=8.0Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 4.82 (s, 2H),4.03 (s, 3H), 3.47 (s, 3H), 2.71 (s, 3H).

Example 2604-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 260A: 2-bromo-4-chlorobenzo[d]thiazole

Copper (II) bromide (134 mg, 0.600 mmol) and4-chlorobenzo[d]thiazol-2-amine (100 mg, 0.542 mmol) were solvated inacetonitrile (1 mL) and THF (1 mL). t-Butyl nitrite (0.086 mL, 0.650mmol) was then added at room temperature. After 30 min, the reactionmixture was dilute with EtOAc and washed with 1.0 M HCl followed bybrine. The crude material was concentrated and purified by ISCO flashchromatography (0-5% EtOAc/Hex over 20 min, 24 g silica gel cartridge,product at 2.5%.) to afford Intermediate 260A (88 mg, 0.279 mmol, 65.4%yield). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 248.0. 250.0, 252.1(M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.72 (d, J=7.9 Hz, 1H), 7.52(d, J=7.9 Hz, 1H), 7.41-7.33 (m, 1H).

Example 260

Intermediate I-2 (15.1 mg, 0.048 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (2.63mg, 3.22 μmol) and Intermediate 260A (10 mg, 0.040 mmol) were solvatedin DMF (1 mL). Sodium Carbonate (2.0 M in H₂O) (100 μL, 0.200 mmol) wasadded, and the solution was degassed with argon for 10 min. The vial wasthen sealed and heated to 100° C. in the microwave for 30 min. The crudesolution was filtered and purified by preparative HPLC (Method D, 45-85%over 10 minutes) to yield Example 260 (4.6 mg, 0.012 mmol, 30.5% yield).LC-MS: Method H, RT=1.44 min, MS (ESI) m/z: 356.0, 358.0 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.88 (s, 1H), 8.19 (d, J=7.7 Hz, 1H),8.11 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 4.83 (s,2H), 3.47 (s, 3H), 2.72 (s, 3H).

Example 2612-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole

Intermediate 261A: 2-bromo-4-methylbenzo[d]thiazole

Copper (II) bromide (122 mg, 0.546 mmol) and2-bromo-4-methylbenzo[d]thiazole (100 mg, 0.609 mmol) were solvated inacetonitrile (1 mL) and THF (1 mL). t-Butyl nitrite (0.096 mL, 0.728mmol) was then added at room temperature. After 30 min, the reactionmixture was dilute with EtOAc and washed with 1.0 M HCl followed bybrine. The crude material was concentrated and purified by ISCO flashchromatography (0-5% EtOAc/Hex over 20 min, 24 g silica gel cartridge,product at 2.5%.) to afford Intermediate 261A (88 mg, 0.386 mmol, 63.6%yield). LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 227.9, 229.9 (M+H)⁺.¹H NMR (400 MHz, CHLOROFORM-d) δ 7.64 (dt, J=7.7, 0.8 Hz, 1H), 7.34-7.27(m, 2H), 2.72 (s, 3H).

Example 261

Intermediate I-2 (16.7 mg, 0.053 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (2.53mg, 3.10 μmol) and Intermediate 261A (10 mg, 0.044 mmol) were solvatedin DMF (1 mL). Sodium Carbonate (2.0 M in H₂O) (100 μL, 0.200 mmol) wasadded, and the solution was degassed with argon for 10 min. The vial wasthen sealed and heated to 100° C. in the microwave for 30 min. The crudesolution was filtered and purified by preparative HPLC (Method D, 55-85%over 10 minutes) to yield Example 261 (4.5 mg, 0.013 mmol, 29.1% yield).LC-MS: Method H, RT=1.52 min, MS (ESI) m/z: 336.1 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 8.02-7.97 (m,1H), 7.38 (d, J=3.9 Hz, 2H), 4.82 (s, 2H), 3.47 (s, 3H), 2.81 (s, 3H),2.71 (s, 3H).

Example 2622-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methyl-6-(trifluoromethoxy)benzo[d]thiazole

Intermediate 262A: 4-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-amine

To a solution of 2-methyl-4-(trifluoromethoxy)aniline (150 mg, 0.785mmol) in acetonitrile (3.924 mL) was added ammonium thiocyanate (90 mg,1.177 mmol) followed by benzyltrimethylammonium tribromide (306 mg,0.785 mmol) causing the reaction mixture to become a bright yellow,heterogeneous suspension. The reaction mixture was allowed to stir atroom temperature overnight. After 13 h, the reaction mixture was dilutedwith EtOAc and washed with saturated NaHCO₃ followed by brine. Thebright yellow organic phase was dried over MgSO₄, filtered andconcentrated. The resulting crude mixture was purified by ISCO (24 gColumn, 0-70% EtOAc/Hex, 18 min. Product at 37%) to give Intermediate262A (112 mg, 0.451 mmol, 57.5% yield) as a white powder. LC-MS: MethodH, RT=1.03 min, MS (ESI) m/z: 249.1 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.32 (s, 1H), 7.02 (s, 1H), 5.24 (br. s., 2H), 2.57 (s,3H). ¹⁹F NMR (376 MHz, CHLOROFORM-d) δ −58.12 (s, 1F).

Intermediate 262B: 2-bromo-4-methyl-6-(trifluoromethoxy)benzo[d]thiazole

Copper (II) bromide (100 mg, 0.479 mmol) and Intermediate 262A (108 mg,0.435 mmol) were solvated in acetonitrile (2 mL). t-Butyl nitrite (0.075mL, 0.566 mmol) was then added at room temperature. After 30 min, thereaction mixture was dilute with EtOAc and washed with 1.0 M HClfollowed by brine. The crude material was concentrated and purified byISCO flash chromatography (0-5% EtOAc/Hex over 20 min, 24 g silica gelcartridge, product at 2.5%.) to afford Intermediate 262B (124 mg, 0.386mmol, 91% yield). LC-MS: Method H, RT=1.42 min, MS (ESI) m/z: 312.0,314.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.51 (s, 1H), 7.17 (s,1H), 2.73 (s, 3H). ¹⁹F NMR (376 MHz, CHLOROFORM-d) δ −57.93 (s, 1F).

Example 262

Intermediate I-2 (15.7 mg, 0.050 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (2.72mg, 3.33 μmol) and Intermediate 262B (13 mg, 0.042 mmol) were solvatedin DMF (1 mL). Sodium carbonate (2.0 M in H₂O) (100 μL, 0.200 mmol) wasadded, and the solution was degassed with argon for 10 min. The vial wasthen sealed and heated to 100° C. in the microwave for 30 min. The crudesolution was filtered and purified by preparative HPLC (Method D,55-100% over 20 minutes) to yield Example 262 (5.9 mg, 0.014 mmol, 33.4%yield). LC-MS: Method H, RT=1.56 min, MS (ESI) m/z: 420.0 (M+H)⁺. ¹H NMR(500 MHz, METHANOL-d₄) δ 9.10 (s, 1H), 8.91 (d, J=1.5 Hz, 1H), 7.98 (s,1H), 7.71 (s, 1H), 7.21 (s, 1H), 4.86 (s, 2H), 3.61 (s, 3H), 2.88 (s,3H), 2.74 (s, 3H).

Preparation of 2-Aminobenzothiazoles

The following 2-aminobenzothiazoles were made according to the followinggeneral procedure, which is analogous to the examples described above

The appropriately substituted aniline (1.0 equiv) was solvated inacetonitrile (0.2 M). To this mixture was added ammonium thiocyanate(1.3 equiv) followed by benzyltrimethylammonium tribromide (1.0 equiv).After being allowed to stir at room temperature for the designatedamount of time, the reaction mixture was diluted with CH₂Cl₂ and washedwith saturated NaHCO₃ followed by brine. The organic phase was driedover MgSO₄, filtered and concentrated before being purified by silicagel chromatography to provide the desired material.

LCMS Retention LCMS Time [M + H]⁺ (Min) Intermediate Structure TimeYield m/z Method H NMR 263A

 3 d 80% 231.1 0.95 ¹H NMR (400 MHz, CHLOROFORM- d) δ 7.26 (s, 1H), 6.95(s, 1H), 6.90 (t, J = 74.8 Hz, 1H), 5.39 (br. s., 2H), 2.40 (s, 3H). ¹⁹FNMR (376 MHz, CHLOROFORM- d) δ −81.04 (s, 1F). 265A

 7 d 24%  233.3, 235.1 1.04 ¹H NMR (400 MHz, CD₃OD-d) δ 7.11 (d, J = 7.5Hz, 1H), 3.87 (s, 3H). 266A

16 h 72% 203.0 205.0 0.94 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.37 (dd, J =8.0, 2.5 Hz, 1H), 7.13 (dd, J = 9.1, 2.5 Hz, 1H). 269A

16 h 77% 217.1 0.89 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.24 (dd, J = 9.6,6.9 Hz, 1H), 4.06 (d, J = 1.1 Hz, 3H). 270A

16 h 64% 199.1 0.74 ¹H NMR (400 MHz, METHANOL-d₄) δ 6.96 (dd, J = 8.1,2.4 Hz, 1H), 6.70 (dd, J = 11.2, 2.4 Hz, 1H), 3.91 (s, 3H). 271A

16 h 73% 229.1 0.79 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.08 (d, J = 7.3 Hz,1H), 4.01 (d, J = 1.1 Hz, 3H), 3.85 (s, 3H). 276A

16 h 67% 195.2 0.66 ¹H NMR (400 MHz, CHLOROFORM- d) δ 7.33 (d, J = 0.7Hz, 1H), 7.04 (s, 1H), 4.97 (br. s., 2H), 3.84 (s, 3H), 2.27 (s, 3H).277A

 4 d 49% 199.1 0.56 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.34 (d, J = 8.4 Hz,1H), 7.10 (d, J = 11.9 Hz, 1H), 3.86 (s, 3H).

Preparation of 2-Bromobenzothiazoles

The following 2-bromobenzothiazoles were made according to the followinggeneral procedure, which is analogous to the examples described above

The appropriately substituted 2-aminobenzothiazole (1.0 equiv) wassuspended in acetonitrile (0.2 M). To this mixture was added copper (II)bromide (1.0 equiv) followed by t-butyl nitrite (1.3 equiv). After beingallowed to stir at room temperature for 30 min, the reaction mixture wasdiluted with EtOAc and washed with 1.0 M HCl followed by brine. Theorganic phase was dried over MgSO₄, filtered and concentrated beforebeing purified by silica gel chromatography to provide the desiredmaterial.

LCMS Retention LCMS Time [M + H]⁺ (Min) Intermediate Structure Yield m/zMethod H NMR 263B

64% 294.1, 296.1  1.24 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.45 (s, 1H),7.10 (s, 1H), 7.04 (t, J = 74.4 Hz, 1H), 2.48 (s, 3H). 264A

45% 272.1, 274.1  1.22 ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (d, J = 1.3Hz, 1H), 8.16 (dd, J = 8.6, 1.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 3.98(s, 3H). 265B

28% 295.9, 297.9, 298.9  1.32 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.22 (d,J = 7.3 Hz, 1H), 3.99 (s, 3H). 266B

62% 265.9, 267.9, 270.0  1.22 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.49-7.42(m, 1H), 7.37-7.30 (m, 1H). 268A

44% 278.0, 280.0, 282.0  1.22 ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (s,1H), 7.30 (s, 1H), 3.98 (s, 4H). 269B

60% 278.1, 280.1  1.21 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.27 (dd, J =6.4, 2.6 Hz, 1H), 4.33 (d, J = 2.0 Hz, 3H). 270B

49% 262.1, 264.1  1.11 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.09 (dd, J =7.7, 2.2 Hz, 1H), 6.70 (dd, J = 10.9, 2.3 Hz, 1H), 4.03 (s, 3H). 271B

53% 292.1, 294.1  1.14 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.00 (d, J = 7.0Hz, 1H), 4.28 (d, J = 2.0 Hz, 3H), 3.95 (s, 3H). 272A

88% 232.0, 234.0  1.17 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.95 (dd, J =9.0, 4.8 Hz, 1H), 7.51 (dd, J = 7.9, 2.4 Hz, 1H), 7.23 (appar. td, J =8.9, 2.6 Hz, 1H). 273A

91% 232.0, 234.0  1.17 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (d, J = 8.1Hz, 1H), 7.40 (appar. td, J = 8.1, 4.6 Hz, 1H), 7.20 (dd, J = 9.6, 8.7Hz, 1H). 274A

73% 248.0, 250.1, 252.1  1.25 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.91 (d,J = 8.6 Hz, 1H), 7.82-7.79 (m, 1H), 7.45 (dd, J = 8.7, 2.1 Hz, 1H). 275A

73% 281.9, 283.9  1.32 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.71 (d, J = 1.8Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H). 276B

74% 258.1, 260.1  1.05 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.71 (d, J = 0.7Hz, 1H), 7.16 (s, 1H), 3.89 (s, 3H), 2.32 (d, J = 0.7 Hz, 3H). 277B

45% 262.0, 264.0  0.96 ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.69 (d, J =11.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 3.96 (s, 3H).

Preparation of Quinoxaline-Benzothiazole Examples

The following Quinoxaline-Benzothiazole adducts were made according tothe following general procedure, which is analogous to the examplesdescribed above

The appropriately substituted 2-bromobenzothiazole (1.0 equiv),PdCl₂(dppf)-CH₂Cl₂ adduct (0.08 equiv), and the appropriate boronic acidor ester (1.0 equiv) were solvated in DMF (0.05 M). A 2.0 M solution ofaqueous sodium carbonate (4.0 equiv) was then added, and the mixture wasdegassed by bubbling argon through the solution for 10 min. The vial wasthen sealed and heated to 100° C. in the microwave for 30 min. The crudesolution was filtered and purified by preparative HPLC to yield thedesired example.

LCMS LCMS RT HPLC [M + (Min) Prep H]⁺ Method Method Ex Structure B(OR)₂Br—Bzt m/z H D NMR 263

I-2 263B 402.2 1.43 50-90% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (s,1H), 8.85 (d, J = 1.7 Hz, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.68 (t, J =74.3 Hz, 1H), 7.21 (s, 1H), 4.82 (s, 2H), 3.47 (s, 3H), 2.71 (s, 3H)[another (s, 3H) was buried under DMSO at 2.5 ppm]. 264

I-2 264A 380.2 1.35 55-100% 11 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (s,1H), 8.92 (d, J = 1.7 Hz, 1H), 8.87 (d, J = 1.7 Hz, 1H), 8.23 (d, J =8.8 Hz, 1H), 8.15-8.10 (m, 2H), 4.83 (s, 2H), 3.93 (s, 3H), 3.48 (s,3H), 2.71 (s, 3H). 265

I-2 265B 404.1 406.1 1.43 70-100% 10 min ¹H NMR (400 MHz, CHLOROFORM- d)δ 9.10 (s, 1H), 8.97 (d, J = 1.5 Hz, 1H), 8.00 (s, 1H), 7.30-7.27 (m,1H- under CDCl₃), 4.86 (s, 2H), 4.02 (s, 3H), 3.59 (s, 3H), 2.73 (s,3H). 266

I-2 266B  374.1, 376.1 1.45 55-100% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ9.11 (s, 1H), 8.84 (s, 1H), 8.14 (d, J = 8.3 Hz, 1H), 8.11 (s, 1H), 7.72(d, J = 8.8 Hz, 1H), 4.84 (s, 2H), 3.49 (s, 3H), 2.72 (s, 3H). 267

I-2 I-41 388.2 1.34 50-90% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (br.s., 1H), 8.81 (br. s., 1H), 8.06 (br. s., 1H), 7.86 (d, J = 5.8 Hz, 1H),4.83 (br. s., 2H), 4.00 (br. s., 3H), 3.49 (br. s., 3H), 2.70 (br. s.,3H). 268

I-2 268A  385.5, 387.5 1.32 50-90% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ9.11 (br. s., 1H), 8.79 (br. s., 1H), 8.20 (br. s., 1H), 8.06 (br. s.,1H), 7.99 (br. s., 1H), 4.83 (br. s., 2H), 3.99 (br. s., 3H), 3.49 (br.s., 3H), 2.69 (br. s., 3H). 269

I-2 269B 388.1 1.40 55-90% 25 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (br.s., 1H), 8.86 (br. s., 1H), 8.11 (br. s., 1H), 8.03 (br. s., 1H), 4.83(br. s., 2H), 4.44 (br. s., 3H), 3.48 (br. s., 3H), 2.72 (br. s., 3H).270

I-2 270B 370.2 1.30 45-85% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s,1H), 8.79 (s, 1H), 8.05 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.05 (d, J =9.6 Hz, 1H), 4.81 (s, 2H), 4.04 (s, 3H), 3.46 (s, 3H), 2.69 (s, 3H). 271

I-2 271B 400.2 1.30 45-85% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (s,1H), 8.80 (d, J = 1.7 Hz, 1H), 8.04 (s, 1H), 7.67 (d, J = 7.4 Hz, 1H),4.81 (s, 2H), 4.34 (s, 3H), 3.94 (s, 3H), 3.47 (s, 3H), 2.69 (s, 3H).272

I-2 272A 340.1 1.38 35-75% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (s,1H), 8.85 (s, 1H), 8.17 (dd, J = 8.9, 4.8 Hz, 1H), 8.13 (d, J = 8.5 Hz,1H), 8.09 (s, 1H), 7.46 (td, J = 8.9, 2.1 Hz, 1H), 4.83 (s, 2H), 3.48(s, 3H), 2.70 (s, 3H). 273

I-2 273A 340.1 1.37 40-80% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (s.,1H), 8.90 (s., 1H), 8.12 (s., 1H), 8.06 (d, J = 7.2 Hz, 1H), 7.52 (s.,1H), 7.47-7.39 (m, J = 9.6 Hz, 1H), 4.84 (s., 2H), 3.49 (s., 3H), 2.72(s., 3H). 274

I-2 274A  356.3, 358.2 1.47 60-100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ9.13 (s, 1H), 8.89 (d, J = 1.9 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.15(d, J = 8.8 Hz, 1H), 8.11 (s, 1H), 7.62 (dd, J = 8.5, 2.2 Hz, 1H), 4.84(s, 2H), 3.48 (s, 3H), 2.71 (s, 3H). 275

I-2 275A  390.1,  392.0, 394.1 1.57 60-100% 20 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.14 (s, 1H), 8.88 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.84(s, 1H), 4.84 (s, 2H), 2.73 (s, 2H) [another (s, 3H) was buried underH₃O at 3.5 ppm]. 276

I-2 276B 438.2 1.16 45-85% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s,1H), 8.79 (s, 1H), 8.02 (br. s., 1H), 7.91 (s, 1H), 7.71 (s, 1H), 4.82(s, 2H), 3.93 (s, 3H), 3.49 (s, 3H), 2.69 (s, 3H), 2.34 (s, 3H). 277

I-2 277B 370.2 1.13 45-95% 15 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (br.s., 1H), 8.81 (br. s., 1H), 8.06 (br. s., 1H), 7.99 (d, J = 9.6 Hz, 2H),4.83 (br. s., 2H), 3.98 (br. s., 3H), 3.49 (br. s., 3H), 2.70 (br. s.,3H). 278

I-9 I-41 374.1 1.49 55-95% 15 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (br.s., 1H), 8.59 (br. s., 1H), 7.92-7.76 (m, 2H), 4.09 (br. s., 3H), 3.99(br. s., 3H), 2.65 (br. s., 3H). 279

I-9 276B 438.2 1.16 45-80% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (s,1H), 8.59 (d, J = 1.9 Hz, 1H), 7.90 (s, 1H), 7.83 (d, J = 0.8 Hz, 1H),7.70 (s, 1H), 4.10 (s, 3H), 3.93 (s, 3H), 2.65 (s, 3H), 2.33 (s, 3H).280

I-9 277B 356.2 1.22 60-100% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (s,1H), 8.60 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 6.6 Hz, 1H), 7.97 (d, J =3.0 Hz, 1H), 7.85 (s, 1H), 4.10 (s, 3H), 3.97 (s, 3H), 2.65 (s, 3H). 281

I-2 I-40 352.3 1.24 40-80% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.76 (br.s., 1H), 9.08 (s, 1H), 8.79 (d, J = 1.7 Hz, 1H), 8.02 (s, 1H), 7.28 (d,J = 2.2 Hz, 1H), 6.87 (d, J = 1.4 Hz, 1H), 4.82 (s, 2H), 3.48 (s, 3H),2.73 (s, 3H), 2.70 (s, 3H). 282

I-9 I-43  390.0, 392.0 1.52 70-100% 15 min ¹H NMR (500 MHz, DMSO-d₆) δ8.78 (br. s., 1H), 8.63 (br. s., 1H), 7.97 (br. s., 1H), 7.89 (br. s.,1H), 4.10 (br. s., 3H), 3.99 (br. s., 3H), 2.67 (br. s., 3H). 283

I-2 I-43  404.1, 406.1 1.16 45-80% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ9.13 (s, 1H), 8.84 (s, 1H), 8.10 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 4.84(s, 2H), 4.01 (s, 3H), 3.49 (s, 3H), 2.72 (s, 3H). 284

I-2 I-47 380.2 1.48 70-100% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s,1H), 8.84 (d, J = 1.9 Hz, 1H), 8.03 (d, J = 0.8 Hz, 1H), 7.58 (s, 1H),4.83 (s, 2H), 3.91 (s, 3H), 3.49 (s, 3H), 2.77 (s, 3H), 2.71 (s, 3H),2.27 (s, 3H). 285

I-9 I-52 428.1 1.20 60-100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (s,1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 7.7 Hz, 1H), 4.10 (s, 3H),3.75 (s, 3H), 2.90 (s, 3H), 2.75 (s, 3H). 286

I-2 I-52 442.2 1.04 45-85% 15 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (s,1H), 8.83 (d, J = 1.4 Hz, 1H), 8.04 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H),5.00 (s, 2H), 4.82 (s, 2H), 3.76 (s, 3H), 3.48 (s, 3H), 2.72 (d, J = 1.4Hz, 3H), 2.70 (s, 3H). 287

I-9 I-57  448.1, 450.1 1.18 60-100% 15 min ¹H NMR (500 MHz, DMSO-d₆) δ9.09 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.04 (s, 1H), 7.77 (d, J = 8.3Hz, 1H), 4.82 (s, 2H), 3.76 (s, 3H), 3.48 (s, 3H), 2.72 (d, J = 1.4 Hz,3H), 2.70 (s, 3H). 288

I-9 I-53 400.2 1.08 45-80% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s,1H), 8.61 (s, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 4.96 (t, J =5.4 Hz, 1H), 4.17 (t, J = 4.8 Hz, 2H), 4.09 (s, 3H), 3.82 (q, J = 4.8Hz, 2H), 2.70 (s, 3H), 2.65 (s, 3H). 289

I-2 I-53 414.2 0.89 30-70% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (s,1H), 8.82 (s, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 4.96 (t, J =5.4 Hz, 1H), 4.82 (s, 2H), 4.17 (t, J = 5.0 Hz, 2H), 3.82 (q, J = 5.1Hz, 2H), 3.49 (s, 3H), 2.70 (s, 6H). 290

I-2 I-46 370.1 0.93 45-85% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.07 (s,1H), 8.81 (d, J = 1.1 Hz, 1H), 8.02 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H),4.82 (s, 2H), 3.48 (s, 3H), 2.70 (s, 3H), 2.69 (d, J = 1.1 Hz, 3H). 291

I-2 I-44  390.1, 392.0 1.27 30-70% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ9.07 (s, 1H), 8.79 (d, J = 1.4 Hz, 1H), 8.04 (s, 1H), 7.63 (d, J = 7.7Hz, 1H), 4.82 (s, 2H), 3.48 (s, 3H), 2.70 (s, 3H). 292

I-2 I-57  462.1, 464.1 1.04 30-65% 10 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.12 (s, 1H), 8.84 (s, 1H), 8.10 (s, 1H), 8.03 (d, J = 7.7Hz, 1H), 5.07 (s, 2H), 4.84 (s, 2H), 3.77 (s, 3H), 3.49 (s, 3H), 2.72(s, 3H). 293

I-2 I-59  434.1, 436.1 0.89 35-70% 10 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.09 (s, 1H), 8.79 (s, 1H), 8.05 (s, 1H), 8.00 (d, J = 7.7Hz, 1H), 5.00 (t, J = 5.4 Hz, 1H), 4.82 (s, 2H), 4.22 (t, J = 4.8 Hz,2H), 3.83 (q, J = 5.0 Hz, 2H), 3.49 (s, 3H), 2.70 (s, 3H). 294

I-9 I-45 370.2 1.30 55-95% 10 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆)δ 8.76 (s, 1H), 8.64 (s, 1H), 7.85 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H),4.10 (s, 3H), 3.95 (s, 3H), 2.71 (s, 3H), 2.66 (s, 3H). 295

I-2 I-45 384.1 1.17 50-85% 10 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆)δ 9.12 (s, 1H), 8.86 (s, 1H), 8.06 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H),4.83 (s, 2H), 3.96 (s, 3H), 3.49 (s, 3H), 2.72 (s, 6H). 296

I-2 I-49 438.1 1.14 60-100% 15 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (s,1H), 8.84 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 4.94 (s, 2H), 4.82 (s,2H), 3.76 (s, 3H), 3.49 (s, 3H), 2.78 (s, 3H), 2.71 (s, 3H), 2.33 (s,3H). 297

I-2 I-51 410..2 1.30 45-90% 12 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆)δ 9.09 (s, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.56 (s, 1H), 4.90 (t, J =5.4 Hz, 1H), 4.82 (s, 2H), 4.11 (br. s., 2H), 3.82 (d, J = 4.7 Hz, 2H),3.48 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H), 2.29 (s, 3H). 298

I-2 I-56  400.1, 402.1 1.41 70-100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ9.12 (s, 1H), 8.83 (s, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 4.84 (s, 2H),3.96 (s, 3H), 3.49 (s, 3H), 2.72 (s, 3H), 2.41 (s, 3H). 299

I-9 I-56  386.1, 388.1 1.50 70-100% 15 min ¹H NMR (500 MHz, DMSO-d₆) δ8.77 (s, 1H), 8.61 (d, J = 1.7 Hz, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 4.10(s, 3H), 3.95 (s, 3H), 2.67 (s, 3H), 2.40 (s, 3H). 300

I-2 I-54 395.8 1.06 55-100% 15 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (s,1H), 8.85 (br. s., 1H), 8.03 (br. s., 1H), 7.69 (s, 1H), 5.20 (br. s.,2H), 5.10-5.04 (m, 1H), 4.82 (s, 2H), 3.92 (s, 3H), 3.48 (s, 3H), 2.71(s, 3H), 2.37 (s, 3H). 301

I-9 I-54 381.8 1.16 50-100% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (s,1H), 8.62 (d, J = 1.7 Hz, 1H), 7.81 (s, 1H), 7.65 (s, 1H), 5.18 (d, J =5.2 Hz, 2H), 5.09-5.02 (m, 1H), 4.08 (s, 3H), 3.91 (s, 3H), 2.65 (s,3H), 2.36 (s, 3H). 302

I-9 I-62 538.1 1.21 60-100% 13 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.15(br. s., 1H), 8.75 (s, 1H), 8.62 (s, 1H), 8.30 (br. s., 1H), 8.04 (d, J= 7.4 Hz, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.19- 7.12 (m, 1H), 4.55 (br.s., 2H), 4.43 (br. s., 2H), 4.10 (s, 3H), 2.70 (s, 3H), 2.66 (s, 3H).303

I-2 I-62 552.1 1.04 45-100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.15(br. s., 1H), 9.11 (s, 1H), 8.84 (s, 1H), 8.30 (br. s., 1H), 8.05 (br.s., 1H), 7.97 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.16 (dd, J = 8.8, 3.0Hz, 1H), 4.83 (s, 2H), 4.55 (d, J = 4.4 Hz, 2H), 4.45 (d, J = 3.6 Hz,2H), 3.49 (s, 3H), 2.90 (s, 3H), 2.75 (s, 3H). 304

I-9 I-63  558.1, 560.1 1.18 70-100% 12 min ¹H NMR (400 MHz, THF) δ 8.83(d, J = 1.5 Hz, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 8.18-8.08 (m, 1H), 7.84(s, 1H), 7.77 (d, J = 7.3 Hz, 1H), 6.95 (dd, J = 8.8, 3.5 Hz, 1H),4.64-4.58 (m, 2H), 4.52-4.46 (m, 2H), 4.15 (s, 3H), 2.70 (s, 3H). 305

I-2 I-63  572.1, 574.1 1.03 50-100% 10 min ¹H NMR (500 MHz, CHLOROFORM-d) δ 9.11 (s, 1H), 9.00 (s, 1H), 8.18 (br. s., 1H), 8.05 (s, 3H), 6.96(dd, J = 8.8, 3.0 Hz, 1H), 4.88 (s, 2H), 4.69-4.64 (m, 2H), 4.48-4.41(m, 2H), 3.62 (s, 3H), 2.76 (s, 3H).

Example 3062-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazol-6-ol

Intermediate 306A: 2-bromo-6-ethoxy-4-methylbenzo[d]thiazole

To a solution of Intermediate I-40 (18 mg, 0.074 mmol) solvated in DMF(1 mL) was added potassium carbonate (51.0 mg, 0.369 mmol) followed byiodoethane (0.018 mL, 0.221 mmol). The reaction mixture was allowed tostir at room temperature overnight. After 15 hours, the reaction mixturewas diluted with hexanes and extracted with water. The organic phase wasconcentrated in vacuo to provide Intermediate 306A (18 mg, 0.066 mmol,90% yield) which was used without further purification. LC-MS: Method H,RT=1.31 min, MS (ESI) m/z: 272.1, 274.1 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.07 (d, J=2.4 Hz, 1H), 6.87 (dd, J=2.4, 0.7 Hz, 1H),4.06 (q, J=7.0 Hz, 2H), 2.66 (s, 3H), 1.45 (t, J=7.0 Hz, 3H).

Example 306

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 306A with Intermediate I-2 afforded Example 306 in 43%yield following purification by preparative HPLC (Method D, 60-100% over10 min). LC-MS: Method H, RT=1.49 min, MS (ESI) m/z: 380.3 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.80 (d, J=1.9 Hz, 1H), 8.03 (s,1H), 7.53 (d, J=2.2 Hz, 1H), 7.00 (s, 1H), 4.81 (s, 2H), 4.12 (q, J=6.9Hz, 2H), 3.47 (s, 3H), 2.75 (s, 3H), 2.69 (s, 3H), 1.38 (t, J=7.0 Hz,3H).

Example 3076-(benzyloxy)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4-methylbenzo[d]thiazole

Intermediate 307A: 6-(benzyloxy)-2-bromo-4-methylbenzo[d]thiazole

To a solution of Intermediate I-40 (18 mg, 0.074 mmol) solvated in DMF(1 mL) was added potassium carbonate (51.0 mg, 0.369 mmol) followed bybenzyl bromide (0.013 mL, 0.111 mmol). The reaction mixture was allowedto stir at room temperature overnight. After 15 hours, the reactionmixture was diluted with hexanes and extracted with water. The organicphase was concentrated in vacuo to provide Intermediate 307A (23 mg,0.066 mmol, 91% yield) which was used without further purification.LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 334.1, 336.1 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.44-7.20 (m, 5H), 7.06 (d, J=2.2 Hz, 1H),6.89 (s, 1H), 5.02 (s, 2H), 2.59 (s, 3H).

Example 307

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 307A with Intermediate I-2 afforded Example 307 in 48%yield following purification by preparative HPLC (Method D, 55-100% over10 min). LC-MS: Method H, RT=1.48 min, MS (ESI) m/z: 442.3 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.80 (s, 1H), 8.02 (s, 1H), 7.63(d, J=2.2 Hz, 1H), 7.51 (d, J=7.4 Hz, 2H), 7.42 (t, J=7.6 Hz, 2H),7.38-7.32 (m, 1H), 7.09 (s, 1H), 5.20 (s, 2H), 4.81 (s, 2H), 3.46 (s,3H), 2.75 (s, 3H), 2.69 (s, 3H).

Example 308(2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)methanol

Intermediate 308A: ethyl 2-bromobenzo[d]thiazole-6-carboxylate

This example was prepared according to the general procedure for2-aminobenzothiazoles described in the table above. Thus, reaction ofethyl 2-aminobenzo[d]thiazole-6-carboxylate afforded Intermediate 308Ain 98% yield. LC-MS: Method A, RT=2.06 min, MS (ESI) m/z: 286.0, 288.0(M+H)⁺. ¹H NMR (500 MHz, CHLOROFORM-d) δ 8.56 (d, J=1.4 Hz, 1H), 8.18(dd, J=8.5, 1.7 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 4.45 (q, J=7.2 Hz, 2H),1.45 (t, J=7.2 Hz, 3H).

Intermediate 308B: (2-bromobenzo[d]thiazol-6-yl)methanol

Intermediate 308A (0.85 g, 2.97 mmol) was dissolved in THF (20 mL) andcooled to 0° C. 1.0 M Super-Hydride in THF (6.54 mL, 6.54 mmol) wasadded dropwise to this cooled solution. After stirring at 0° C. for 1 h,the reaction was quenched with saturated ammonium chloride and thendiluted with EtOAc. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated. The crude product waspurified by silica gel chromatography (24 g, 5-60% EtOAc/Hexanes, 18min) to give Intermediate 308B (0.5 g, 2.048 mmol, 69.0% yield) as awhite solid. LC-MS: Method A, RT=1.54 min, MS (ESI) m/z: 244.0 and 246.0(M+H)⁺. ¹H NMR (500 MHz, CHLOROFORM-d) δ 7.93 (d, J=8.5 Hz, 1H), 7.70(d, J=0.8 Hz, 1H), 7.39 (dd, 1.5 Hz, 1H), 5.08 (s, 2H).

Example 308

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 308B with Intermediate I-2 afforded Example 308 in 19%yield following purification by preparative HPLC (Method D, 20-60% over10 min). LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: 352.2 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.88 (d, J=1.7 Hz, 1H), 8.13 (s,1H), 8.10 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 7.54 (dd, J=8.5, 1.4 Hz, 1H),5.38 (t, J=5.8 Hz, 1H), 4.83 (s, 2H), 4.69 (d, J=5.8 Hz, 2H), 3.49 (s,3H), 2.71 (s, 3H).

Example 3096-(methoxymethyl)-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 309A: 2-bromo-6-(methoxymethyl)benzo[d]thiazole

Intermediate 308B (52 mg, 0.213 mmol) was solvated in THF (2.1 mL) andcooled to 0° C. Sodium Hydride (42.6 mg, 1.065 mmol) was added, causingeffervescence. After 5 minutes, methyl iodide (0.067 mL, 1.065 mmol) wasadded. The mixture was then allowed to warm to room temperature andstirred for 10 minutes until all of the bubbling subsided. The reactionwas quenched with saturated NH₄Cl and diluted with EtOAc. The organicphase was extracted, washed with brine, dried over MgSO₄ andconcentrated. The crude material was purified by ISCO (12 g, 0-20%EtOAc/Hexanes, 18 min. Product at 8%) to afford Intermediate 309A (10mg, 0.039 mmol, 18% yield). LC-MS: Method H, RT=1.19 min, MS (ESI) m/z:258.1, 260.1 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.96 (d, J=8.4 Hz,1H), 7.81 (d, J=0.7 Hz, 1H), 7.43 (dd, J=8.4, 1.5 Hz, 1H), 4.58 (s, 2H),3.44 (s, 3H).

Example 309

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 309A with Intermediate I-2 afforded Example 309 in 27%yield following purification by preparative HPLC (Method D, 45-85% over10 min). LC-MS: Method H, RT=1.33 min, MS (ESI) m/z: 366.3 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.88 (d, J=1.4 Hz, 1H), 8.15 (s,1H), 8.12 (d, J=8.3 Hz, 1H), 8.09 (s, 1H), 7.54 (d, J=8.3 Hz, 1H), 4.84(s, 2H), 4.61 (s, 2H), 3.49 (s, 3H), 3.37 (s, 3H), 2.71 (s, 3H).

Example 3106-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5-ol

Intermediate 310A: 3-((tert-butyldimethylsilyl)oxy)-4-methoxyaniline

5-amino-2-methoxyphenol (500 mg, 3.59 mmol) was solvated in DMF (3.00mL) and DCM (15.000 mL). To this solution was added TBDMS-Cl (596 mg,3.95 mmol) followed by imidazole (269 mg, 3.95 mmol) at roomtemperature. After 2 h, the reaction was quenched with saturated NaHCO₃and extracted 2× with DCM. The organic phase was concentrated andpurified by ISCO (80 g, 0-100% EtOAc/Hexanes, 33 min. Product at 35%) togive Intermediate 310A (576 mg, 1.591 mmol, 44.3% yield). LC-MS: MethodH, RT=0.99 min, MS (ESI) m/z: 254.2 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 6.69 (d, J=8.4 Hz, 1H), 6.31-6.24 (m, 2H), 3.73 (s, 3H),3.38 (br. s., 2H), 1.00 (s, 9H), 0.16 (s, 6H).

Intermediate 310B:5-((tert-butyldimethylsilyl)oxy)-6-methoxybenzo[d]thiazol-2-amine

This example was prepared according to the general procedure for thesynthesis of 2-aminobenzothiazoles described in the table above. Thus,Intermediate 310A was reacted to afford Intermediate 310B as a viscousbrown oil (36% Yield). LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 311.2(M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.11 (s, 1H), 7.07 (s, 1H),4.93 (br. s., 2H), 3.83 (s, 3H), 1.02 (s, 9H), 0.18 (s, 6H).

Intermediate 310C:2-bromo-5-((tert-butyldimethylsilyl)oxy)-6-methoxybenzo[d]thiazole

This intermediate was prepared according to the general procedure forthe synthesis of 2-bromobenzothiazoles described in the table above.Thus, Intermediate 310B was reacted to afford Intermediate 310C as apurple oil (53% yield). LC-MS: Method H, RT=1.50 min, MS (ESI) m/z:374.0, 376.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.08 (s, 1H), 6.99(s, 1H), 3.69 (s, 3H), 0.84 (s, 9H), 0.00 (s, 6H).

Intermediate 310D: 2-bromo-6-methoxybenzo[d]thiazol-5-ol

To a solution of Intermediate 310C (76 mg, 0.203 mmol) in THF (2030 μl)was added TBAF (1.0 M in THF) (264 μl, 0.264 mmol) at room temperature.After 10 min, the reaction mixture was diluted with EtOAc and washedwith brine. The organic phase was concentrated and purified by ISCO (12g, 0-70% EtOAc/Hexanes, 18 min. Product at 28%) to give Intermediate310D (28 mg, 0.108 mmol, 53.0% yield) as a white solid. LC-MS: Method H,RT=1.05 min, MS (ESI) m/z: 260.0, 262.0 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.53 (s, 1H), 7.21 (s, 1H), 5.80 (s, 1H), 3.99 (s, 3H).

Example 310

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 310D with Intermediate I-2 afforded Example 310 in 36%yield following purification by preparative HPLC (Method D, 15-55% over20 min). LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 368.1 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.46 (br. s., 1H), 9.09 (s, 1H), 8.79 (s, 1H),8.01 (s, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 4.82 (s, 2H), 3.91 (s, 3H),3.48 (s, 3H), 2.68 (s, 3H).

Example 3115,6-dimethoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 311A: 2-bromo-5,6-dimethoxybenzo[d]thiazole

To a solution of Intermediate 310D (14 mg, 0.054 mmol) solvated in DMF(1 mL) was added potassium carbonate (37.2 mg, 0.269 mmol) followed byiodomethane (10.10 μl, 0.161 mmol). The reaction mixture was allowed tostir at room temperature overnight. After 14 h, the reaction mixture wasdiluted with hexanes and washed with water followed by brine. Theorganic phase was dried over MgSO₄, filtered and concentrated to provideIntermediate 311A (11 mg, 0.040 mmol, 75% yield) as a white solid, whichwas taken on without further purification. LC-MS: Method H, RT=1.13 min,MS (ESI) m/z: 274.0, 276.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.46(s, 1H), 7.22 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H.)

Example 311

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 311A with Intermediate I-2 afforded Example 311 in 30%yield following purification by preparative HPLC (Method D, 30-70% over10 min). LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 382.1 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 7.75(s, 1H), 7.67 (s, 1H), 4.82 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.48(s, 3H), 2.69 (s, 3H).

Example 312(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-5-yl)methanol

Intermediate 312A: 2-methoxy-5-nitrobenzonitrile

To a vessel charged with 2-bromo-1-methoxy-4-nitrobenzene (1 g, 4.31mmol), zinc cyanide (0.506 g, 4.31 mmol), zinc (0.028 g, 0.431 mmol) andpalladium tetrakis (0.174 g, 0.151 mmol) was added DMF (14.37 ml), andthe mixture was sparged with argon for 20 min. The vial was sealed andheated to 90° C. overnight. After 22 h, the black solution was dilutedwith water and EtOAc. The organic phase was extracted, washed withbrine, concentrated and purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 28min. Product at 50%) to provide Intermediate 312A (520 mg, 2.92 mmol,67.7% yield) as an off-white solid. LC-MS: Method H, RT=0.78 min, MS(ESI) m/z: None Observed (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.49(d, J=2.6 Hz, 1H), 8.48-8.43 (m, 1H), 7.10 (d, J=9.2 Hz, 1H), 4.08 (s,3H).

Intermediate 312B: 2-methoxy-5-nitrobenzaldehyde

A solution of Intermediate 312A (520 mg, 2.92 mmol) in Et₂O (23.400 mL)was cooled to 0° C. under an atmosphere of N₂. A solution of DIBAl-H(1.0 M in Toluene) (4.38 mL, 4.38 mmol) was then added dropwise causingbubbling to occur. After 5 min of stirring, the reaction mixture wasallowed to thaw to room temperature. After an additional 3 h, the orangesolution was poured into a mixture of ice and 10 mL of glacial aceticacid. This mixture was stirred while the ice melted, diluted with EtOAcand DI water and then extracted. The organic phase was concentrated andpurified by ISCO (80 g, 0-100% EtOAc/Hexanes, 28 min. Product at 55%) toafford Intermediate 312B (410 mg, 1.811 mmol, 62.0% yield) as a lightorange solid. LC-MS: Method H, RT=0.77 min, MS (ESI) m/z: 182.1 (M+H)⁺.¹H NMR (400 MHz, CHLOROFORM-d) δ 10.46 (s, 1H), 8.71 (d, J=2.9 Hz, 1H),8.45 (dd, J=9.2, 2.9 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 4.08 (s, 3H).

Intermediate 312C: (2-methoxy-5-nitrophenyl)methanol

A solution of Intermediate 312B (410 mg, 2.263 mmol) in Toluene (11.500mL) and THF (11.50 mL) was cooled to −78° C. under an atmosphere of N₂.DIBAL-H (1.0 M in Toluene) (3.40 mL, 3.40 mmol) was then added to thecooled solution dropwise. After the initial bubbling had subsided, thereaction mixture was allowed to thaw to room temperature. After 1 h, thereaction mixture was cooled to 0° C. and quenched with 1.0 M HCl. Theresulting suspension was stirred vigorously for 45 min to fully cleavethe aluminate complex. The mixture was then diluted with EtOAc andextracted. The organic phase was washed with brine, dried over MgSO₄,filtered and concentrated. The resulting crude product was purified byISCO (80 g, 0-100% EtOAc/Hexanes, 33 min. Product at 50%) to giveIntermediate 312C (370 mg, 1.717 mmol, 76% yield) as a light yellowsolid. LC-MS: Method H, RT=0.68 min, MS (ESI) m/z: 184.0 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.29 (d, J=2.9 Hz, 1H), 8.21 (dd, J=9.0, 2.6Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 4.75 (d, J=6.4 Hz, 2H), 3.97 (s, 3H),2.07 (t, J=6.4 Hz, 1H).

Intermediate 312D:tert-butyl((2-methoxy-5-nitrobenzyl)oxy)dimethylsilane

To a solution of Intermediate 312C (370 mg, 1.717 mmol) andtriethylamine (0.479 mL, 3.43 mmol) in DCM (17.200 mL) was added TBS-Cl(336 mg, 2.232 mmol) followed by DMAP (42.0 mg, 0.343 mmol). After 2 h,the reaction mixture was concentrated and the crude material waspurified by ISCO (80 g, 0-20% EtOAc/Hexanes, 28 min. Product at 15%.) togive Intermediate 312D (490 mg, 1.647 mmol, 96% yield) as a yellow oil.LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: None Observed (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.45-8.35 (m, 1H), 8.17 (dd, 2.6 Hz, 1H), 6.88(d, J=8.8 Hz, 1H), 4.75 (s, 2H), 3.94 (s, 3H), 0.99 (s, 9H), 0.15 (s,6H).

Intermediate 312E:3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxyaniline

Degussa grade Pd/C (175 mg, 0.165 mmol) was added to a 250 mL roundbottom flask containing Intermediate 312D (490 mg, 1.647 mmol). Themixture was carefully wet with a few mL of MeOH before adding the totalvolume of solvent (14.0 mL). The head space of the flask was evacuateduntil the solvent began to slightly bubble and then back-filled with N₂.A hydrogen balloon was attached to the flask, and the solution wassparged with H₂ for about 5 minutes through a vent needle. The vent wasremoved and the reaction mixture was stirred vigorously under the H₂atmosphere for 1 h before being filtered over celite to remove the Pd/C.The celite was rinsed with EtOAc, and the filtrate was concentrated toafford Intermediate 312E (430 mg, 1.608 mmol, 98% yield) as a brown oil.LC-MS: Method H, RT=0.81 min, MS (ESI) m/z: 268.3 (M+H)⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 6.88 (d, J=2.9 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H),6.55 (dd, J=8.4, 2.9 Hz, 1H), 4.72 (s, 2H), 3.75 (s, 3H), 3.43 (br. s.,2H), 0.97 (s, 9H).

Intermediate 312F:5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methoxybenzo[d]thiazol-2-amineIntermediate 312G: (2-amino-6-methoxybenzo[d]thiazol-5-yl)methanol

To a solution of Intermediate 312E (430 mg, 1.608 mmol) in acetonitrile(13.700 mL) was added ammonium thiocyanate (159 mg, 2.090 mmol). Themixture was stirred at room temperature for 10 min followed by theaddition of benzyltrimethylammonium tribromide (627 mg, 1.608 mmol).After 3 days the reaction mixture was diluted with saturated NaHCO₃ andextract with EtOAc 3×. The organic phase was dried over MgSO₄, filtered,concentrated and purified by ISCO (40 g, 0-100% EtOAc/Hexanes, 19 min.Product at 50%) to give Intermediate 312F (219 mg, 0.675 mmol, 42.0%yield) as a brown oil. LC-MS: Method H, RT=0.89 min, MS (ESI) m/z: 325.3(M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.69 (s, 1H), 7.06 (s, 1H),4.97 (br. s., 2H), 4.80 (d, J=0.9 Hz, 2H), 3.84 (s, 3H), 0.98 (s, 9H),0.13 (s, 6H). The silica gel column was further flushed (0-20% DCM/MeOH,19 min. Product at 12%) to afford Intermediate 312G (166 mg, 0.790 mmol,49.1% yield) as a tan solid. LC-MS: Method H, RT=0.47 min, MS (ESI) m/z:211.2 (M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.41 (s, 1H), 7.21 (s,1H), 4.64 (s, 2H), 3.83 (s, 3H).

Intermediate 312H: (2-bromo-6-methoxybenzo[d]thiazol-5-yl)methanol

To a suspension of Intermediate 312G (160 mg, 0.761 mmol) inacetonitrile (7610 μl) was added copper (II) bromide (170 mg, 0.761mmol) followed by t-Butyl nitrite (131 μl, 0.989 mmol). After 1 h ofstirring, the reaction mixture was diluted with EtOAc, and poured into a1.0 M HCl solution. The organic phase was dried over MgSO₄, filtered,concentrated and purified by ISCO (40 g, 0-70% EtOAc/Hexanes, 19 min.Product at 35%) to afford Intermediate 312H (119 mg, 0.434 mmol, 57.0%yield) as an off-white solid. LC-MS: Method H, RT=0.81 min, MS (ESI)m/z: 274.1, 276.1 (M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.93 (s, 1H),7.50 (s, 1H), 4.71 (d, J=0.7 Hz, 2H), 3.91 (s, 3H).

Example 312

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 312H with Intermediate I-2 afforded Example 312 in 47%yield following purification by preparative HPLC (Method D, 30-70% over20 min). LC-MS: Method H, RT=0.96 min, MS (ESI) m/z: 382.2 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.11 (br. s., 1H), 8.82 (br. s., 1H), 8.08 (br.s., 1H), 8.04 (br. s., 1H), 7.74 (br. s., 1H), 4.83 (br. s., 2H), 4.65(br. s., 2H), 3.92 (br. s., 3H), 3.49 (br. s., 3H), 2.70 (br. s., 3H).

Example 3136-chloro-5-fluoro-4-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 313A: 1-chloro-2-fluoro-3-methoxy-4-nitrobenzene

To a 0° C. solution of 1-chloro-2-fluoro-3-methoxybenzene (1.606 g, 10mmol) in acetic acid (5.00 ml) was added fuming nitric acid (0.933 ml,20.00 mmol) followed by the dropwise addition of sulfuric acid (2.132ml, 40.0 mmol). After 30 min, the reaction mixture was poured into waterand diluted with ethyl acetate. The organic phase was separated andwashed 2× with saturated NaHCO₃ followed by a final brine wash. Theorganic solution was then dried over MgSO₄, filtered, concentrated andpurify by ISCO (120 g, 10-50% EtOAc/Hexanes, 25 min. Desired regioisomereluted first) affording Intermediate 313A (900 mg, 4.38 mmol, 44% yield)as a yellow solid. LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: NoneObserved (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.60 (dd, J=9.0, 2.2Hz, 1H), 7.24 (dd, J=9.0, 6.6 Hz, 1H), 4.11 (d, J=1.8 Hz, 3H).Regiochemistry confirmed through NMR analysis of both regioisomericproducts.

Intermediate 313B: 4-chloro-3-fluoro-2-methoxyaniline

A solution of Intermediate 313A (700 mg, 3.41 mmol) in MeOH (17.000 mL,0.2 M) was added NH₄Cl (3643 mg, 68.1 mmol) and zinc dust (2226 mg, 34.1mmol) was heated to reflux for 1 h. The resulting mixture was allowed tocool to room temperature and the solvent was removed in vacuo. Theresulting residue was diluted with EtOAc and saturated sodiumbicarbonate (0.2 M of each) and stirred vigorously for an additional 1hr. The mixture was filtered over celite, the organic layer wasseparated, washed with brine, dried over MgSO₄, filtered andconcentrated to give Intermediate 313B (466 mg, 2.66 mmol, 78% yield) asa dark brown solid. This material was taken on without furtherpurification. LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 176.1, 178.1(M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.87 (dd, 7.5 Hz, 1H), 6.43(dd, J=8.7, 1.9 Hz, 1H), 3.92 (d, J=1.5 Hz, 3H), 3.49 (s, 2H).

Intermediate 313C: 6-chloro-5-fluoro-4-methoxybenzo[d]thiazol-2-amine

This example was prepared according to the general procedure for2-aminobenzothiazoles described in the table above. Thus, reaction ofIntermediate 313B afforded Intermediate 313C in 21% yield. LC-MS: MethodH, RT=0.99 min, MS (ESI) m/z: 233.1, 235.0 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.30 (d, J=6.2 Hz, 1H), 5.38 (br. s., 2H), 4.15 (d,J=1.8 Hz, 3H).

Intermediate 313D: 6-chloro-5-fluoro-4-methoxybenzo[d]thiazol-2-amine

Intermediate 313D was prepared according to the general procedure for2-bromobenzothiazoles described in the table above. Thus, reaction ofIntermediate 313C afforded Intermediate 313D in 58% yield. LC-MS: MethodH, RT=1.29 min, MS (ESI) m/z: 296.0, 298.0, 299.9 (M+H)⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.50 (d, J=5.7 Hz, 1H), 4.30 (d, J=1.8 Hz, 3H).

Example 313

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 313D with Intermediate I-2 afforded Example 313 in 8%yield following purification by preparative HPLC (Method D, 60-100% over20 min). LC-MS: Method H, RT=1.49 min, MS (ESI) m/z: 404.1, 406.1(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.89 (s, 1H), 8.20 (d,J=6.1 Hz, 1H), 8.13 (br. s., 1H), 4.84 (s, 2H), 4.41 (s, 3H), 3.48 (s,3H), 2.73 (s, 3H).

Example 3144-cyclopropyl-5-fluoro-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Example 283 (19 mg, 0.047 mmol) was solvated in a solution ofcyclopropylzinc(II) bromide (0.5 M in THF, 1411 μl, 0.706 mmol) andtransferred to a microwave vial containing Pd(dppf)₂Cl₂—CH₂Cl₂ adduct(3.84 mg, 4.70 μmol). The solution was sparged with argon for 5 min,sealed and then heated to 100° C. in the microwave. The crude reactionmixture was then concentrated, retaken in DMF, filtered and purified bypreparatory HPLC (Method D, 60-100% over 20 min) to afford Example 314(1.1 mg, 2.69 μmol, 6% yield). LC-MS: Method H, RT=1.47 min, MS (ESI)m/z: 410.1, (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.73 (d,J=1.7 Hz, 1H), 8.05 (s, 1H), 7.75 (d, J=7.7 Hz, 1H), 4.86-4.78 (m, 2H),3.94 (s, 3H), 3.49 (s, 3H), 2.70 (s, 3H), 2.66-2.58 (m, 1H), 1.18-1.13(m, 2H), 0.87 (t, J=6.9 Hz, 2H).

Example 3156-ethoxy-4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 315A: 2-bromo-6-ethoxy-4,5-difluorobenzo[d]thiazole

To a vial charged with Intermediate I-42 (13 mg, 0.049 mmol) and Cs₂CO₃(80 mg, 0.244 mmol) was added DMF (1 mL). The resulting mixture wasvigorously stirred for 5 min before the addition of iodoethane (0.012mL, 0.147 mmol). After 16 h of stirring at room temperature, thereaction mixture was diluted with hexanes and extracted with water. Theorganic phase was dried over MgSO₄, filtered, concentrated and purifiedby ISCO (12 g, 0-20% EtOAc/Hexanes, 16 min. Product at 8%) to affordIntermediate 315A (9 mg, 0.031 mmol, 62.6% yield) as a white solid.LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 294.0, 296.0 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.08 (dd, J=6.6, 2.0 Hz, 1H), 4.16 (q, J=6.9Hz, 2H), 1.51 (t, J=7.0 Hz, 3H).

Example 315

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 315A with Intermediate I-2 afforded Example 315 in 22%yield following purification by preparative HPLC (Method D, 60-100% over20 min). LC-MS: Method H, RT=1.48 min, MS (ESI) m/z: 388.1 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.62 (s, 1H), 7.87 (s, 1H), 7.83(d, J=6.9 Hz, 1H), 4.26 (q, J=6.9 Hz, 2H), 4.10 (s, 3H), 2.66 (s, 3H),1.45 (t, J=7.0 Hz, 3H).

Example 316N-(2-((4,5-difluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide

Intermediate 316A: tert-butyl(2-((2-bromo-4,5-difluorobenzo[d]thiazol-6-yl)oxy)ethyl)carbamate

A solution of Intermediate I-42 (100 mg, 0.376 mmol) andtriphenylphosphine (197 mg, 0.752 mmol) in THF (2 mL) was heated toreflux. To this refluxing mixture was added a pre-mixed solution of DIAD(0.219 mL, 1.128 mmol) and tert-butyl (2-hydroxyethyl)carbamate (182 mg,1.128 mmol) in THF (2 mL) over the course of 2 h via syringe pump. Thecrude reaction mixture was concentrated and purified by ISCO (40 g,0-30% DCM/EtOAc, 22 min, Product at 8%) to afford Intermediate 316A (53mg, 0.130 mmol, 34.5% yield) as a yellow amorphous solid. LC-MS: MethodH, RT=1.25 min, MS (ESI) m/z: 409.0, 411.0 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.11 (dd, J=6.5, 1.9 Hz, 1H), 5.03 (br. s., 1H), 4.14(t, J=5.2 Hz, 2H), 3.60 (q, J=5.4 Hz, 2H), 1.45 (s, 9H).

Intermediate 316B:2((2-bromo-4,5-difluorobenzo[d]thiazol-6-yl)oxy)ethanamine HCl

To a flask charged with Intermediate 316A (53 mg, 0.130 mmol) was added4.0 N HCl in dioxane (2.43 mL, 9.71 mmol) causing a white slurry toimmediately form. After 1 h, the solution was concentrated in vacuo toafford Intermediate 316B as an HCl salt. LC-MS: Method H, RT=0.83 min,MS (ESI) m/z: 265.1, 267.1 (M+H—CH₂CH₂NH₂)⁺. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.59 (dd, J=6.9, 2.1 Hz, 1H), 4.42-4.36 (m, 2H), 3.46 (t,J=4.8 Hz, 2H).

Intermediate 316C:N-(2-((2-bromo-4,5-difluorobenzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide

To a solution of Intermediate 316B (44 mg, 0.127 mmol) in THF (1.5 mL)was added DIEA (0.067 mL, 0.382 mmol) and 3-fluorobenzene-1-sulfonylchloride (37.2 mg, 0.191 mmol). The white slurry was stirred for 1 hrbefore being quenched with water and extracted with EtOAc. The organicphase was further washed with brine, concentrated, and purified by ISCO(12 g, 0-50% EtOAc/Hexanes, 20 min. Product at 38%) to affordIntermediate 316C (53 mg, 0.113 mmol, 89% yield) as a pale yellow,amorphous solid. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z: 467.0,469.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.72-7.67 (m, 1H),7.63-7.56 (m, 1H), 7.51 (td, 5.3 Hz, 1H), 7.31-7.24 (m, 1H), 7.03 (dd,J=6.6, 2.0 Hz, 1H), 5.16 (t, J=6.2 Hz, 1H), 4.16 (t, J=5.1 Hz, 2H),3.53-3.46 (m, 2H).

Example 316

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 316C with Intermediate I-9 afforded Example 316 in 43%yield following purification by preparative HPLC (Method D, 50-100% over20 min). LC-MS: Method H, RT=1.36 min, MS (ESI) m/z: 561.1 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.23 (br.s., 1H), 7.79 (s, 1H), 7.72-7.67 (m, 2H), 7.67-7.61 (m, 2H), 7.48 (td,J=8.5, 1.9 Hz, 1H), 4.18 (t, J=5.1 Hz, 2H), 4.08 (s, 3H), 3.36-3.30 (m,2H-buried under DMSO), 2.62 (s, 3H).

Example 317N-(2-((4,5-difluoro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-3-fluorobenzenesulfonamide

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 316C with Intermediate I-2 afforded Example 317 in 6%yield following purification by preparative HPLC (Method D, 45-90% over20 min). LC-MS: Method H, RT=1.30 min, MS (ESI) m/z: 575.1 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.25-9.04 (m, 1H), 8.83 (br. s., 1H), 8.25 (br.s., 1H), 8.08 (br. s., 1H), 7.79 (d, J=6.1 Hz, 1H), 7.69 (d, J=7.7 Hz,1H), 7.63 (d, J=7.7 Hz, 1H), 7.46 (br. s., 1H), 4.82 (br. s., 2H), 4.20(d, J=4.4 Hz, 2H), 3.49 (d, J=5.0 Hz, 3H), 3.36-3.30 (m, 2H-buried underDMSO) 2.70 (br. s., 3H).

Example 3182-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanol

Intermediate 318A:2-((4-chloro-2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)ethanol

A 20 mL microwave vial was charged with Intermediate I-1 (623 mg, 1.853mmol), Intermediate I-59 (605 mg, 1.853 mmol) and[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (76 mg, 0.093 mmol). These solids weresuspended in a combination of Toluene (11.600 mL), EtOH (3.87 mL) and a2.0 M solution of Na₂CO₃ (1.389 mL, 2.78 mmol). The resulting mixturewas sparged with argon for 10 min, sealed and then heated in a microwaveat 130° C. for 30 min. The crude reaction mixture was diluted with 100mL EtOAc and filtered over celite. The organic solution was concentratedonto celite and purified by ISCO (80 g, 0-100% EtOAc/Hexanes, 36 min.Product dragged from 50%-100%) to afford Intermediate 318A (630 mg,1.382 mmol, 74.6% yield) as a bright yellow solid. LC-MS: Method H,RT=1.13 min, MS (ESI) m/z: 456.0, 458.1 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.76 (d, J=1.8 Hz, 1H), 8.03 (d, J=7.7 Hz, 1H),7.96 (d, J=0.9 Hz, 1H), 7.90 (t, J=71.1 Hz, 1H), 4.99 (t, J=5.5 Hz, 1H),4.22 (t, J=4.8 Hz, 2H), 3.82 (q, J=5.2 Hz, 2H), 2.70 (s, 3H).

Example 318

To a solution of Intermediate 318A (630 mg, 1.382 mmol) in THF (27.600mL) was added a 0.5 M solution of NaOMe in MeOH (27.6 mL, 13.82 mmol).After 1 h of stirring, the reaction mixture was quenched with 1.0 N HCl(27.6 mL) and diluted with EtOAc. The organic phase was washed withbrine, and concentrated in vacuo to afford Example 318 (650 mg, 1.393mmol, 91% yield). The majority of this crude material was taken onwithout further purification, but a small portion was further purifiedby preparative HPLC for characterization (Method D, 45-80% over 13 min,100% for 5 min). LC-MS: Method H, RT=1.05 min, MS (ESI) m/z: 420.1,422.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.61 (d, J=1.8Hz, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.87 (s, 1H), 4.99 (t, J=5.4 Hz, 1H),4.22 (t, J=5.0 Hz, 2H), 4.10 (s, 3H), 3.82 (q, J=5.2 Hz, 2H), 2.67 (s,3H).

Example 3191-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)-2-methylpropan-2-ol

Intermediate 319A:1-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)-2-methylpropan-2-ol

A solution of Intermediate I-49 (16 mg, 0.048 mmol) in THF (1 mL) wascooled to −78° C. To this cold solution was added MeMgBr (3.0 M in Et₂O)(0.162 mL, 0.485 mmol) dropwise. The resulting mixture was allowed towarm to 0° C. Once at 0° C. the reaction was quenched with 1 mL of 1 MHCl. This mixture was then concentrated and purified by ISCO (12 g,0-50% EtOAc/Hexanes, 16 min. Product at 25%,) to afford Intermediate319A (5 mg, 0.015 mmol, 31.2% yield) as a colorless oil. LC-MS: MethodH, RT=1.29 min, MS (ESI) m/z: 330.1, 332.1 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.06 (s, 1H), 3.83 (s, 2H), 2.65 (s, 3H), 2.30 (s, 3H),2.14 (s, 1H), 1.40 (s, 6H).

Example 319

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 319A with Intermediate I-2 afforded Example 319 in 67%yield following purification by preparative HPLC (Method D, 70-100% over10 min). LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 438.2 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.83 (s, 1H), 8.01 (s, 1H), 7.53(s, 1H), 4.82 (s, 2H), 4.71 (s, 1H), 3.83 (s, 2H), 3.49 (s, 3H), 2.77(s, 3H), 2.70 (s, 3H), 2.31 (s, 3H), 1.30 (s, 6H).

Example 3202-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethylmethyl carbonate

Intermediate 320A:2-((2-chloro-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)ethyl methyl carbonate

To a solution of Intermediate I-51 (30 mg, 0.099 mmol) in THF (1 mL) wasadded Hunig's Base (0.087 mL, 0.496 mmol) followed by a solution ofphosgene (15% by wt in toluene) (0.210 mL, 0.298 mmol). After 15 min ofstirring, 1 mL of MeOH was added and the reaction mixture wasconcentrated. The crude residue was purified by ISCO (12 g, 0-30%EtOAc/Hexanes, 16 min. Product at 15%) to afford Intermediate 320A (12mg, 0.038 mmol, 38.3% yield) as a white solid. LC-MS: Method H, RT=0.95min, MS (ESI) m/z: 316.1, 318.1 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.02 (d, J=8.4 Hz, 1H), 4.59-4.53 (m, 2H), 4.25-4.18 (m, 2H), 3.82 (s,3H), 2.63 (d, J=5.1 Hz, 3H), 2.26 (s, 3H).

Example 320

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 320A with Intermediate I-2 afforded Example 320 in 50%yield following purification by preparative HPLC (Method D, 60-100% over15 min). LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 468.2 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.82 (s, 1H), 8.01 (s, 1H), 7.59(s, 1H), 4.82 (s, 2H), 4.54 (br. s., 2H), 4.32 (br. s., 2H), 3.76 (s,3H), 3.49 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H), 2.25 (s, 3H).

Example 3212-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-1-ol(racemate)

Intermediate 321A:2((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-1-ol

This example was prepared in a manner analogous to Intermediate I-51.Thus, Intermediate I-50 (rac) was reacted to afford Intermediate 321A(rac) (91% yield) as an off-white, amorphous solid. LC-MS: Method H,RT=1.26 min, MS (ESI) m/z: 314.0, 316.0 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.14 (s, 1H), 4.57-4.46 (m, 1H), 3.80 (d, J=5.3 Hz, 2H),2.64 (s, 3H), 2.26 (s, 3H), 1.30 (d, J=6.4 Hz, 3H), 1.26 (br. s, 1H).

Example 321

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 321A (rac) with Intermediate I-2 afforded Example 321(rac) in 66% yield following purification by preparative HPLC (Method D,40-75% over 10 min, 100% for 5 min). LC-MS: Method H, RT=0.90 min, MS(ESI) m/z: 423.9 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.83(s, 1H), 8.01 (s, 1H), 7.62 (s, 1H), 4.88 (t, J=5.5 Hz, 1H), 4.82 (s,2H), 4.60-4.48 (m, 1H), 3.66 (dt, J=11.1, 5.3 Hz, 1H), 3.60-3.52 (m,1H), 3.49 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H), 2.27 (s, 3H), 1.30 (d,J=5.8 Hz, 3H).

Example 3221-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-2-ol(racemate)

Intermediate 322A:2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)acetaldehyde

A solution of Intermediate I-51 (20 mg, 0.066 mmol) in DCM (1 mL) wascooled to 0° C. To this cooled mixture was added Dess-Martin Periodinane(84 mg, 0.199 mmol). After 1 h, the solution was allowed to thaw to roomtemperature and stirred vigorously for an additional 5 h. The reactionmixture was then concentrated and the residue was purified by ISCO (12g, 0-50% EtOAc/Hexanes, 16 min. Product at 25%) to afford Intermediate322A (11 mg, 0.037 mmol, 55.4% yield) as a white solid. LC-MS: Method H,RT=1.09 min, MS (ESI) m/z: 317.7, 319.7 (M+H+H₂O)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 9.90 (t, J=1.1 Hz, 1H), 6.93 (s, 1H), 4.62 (d, J=1.1 Hz,2H), 2.69-2.63 (m, 3H), 2.35 (s, 3H).

Intermediate 322B:1-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propan-2-ol (racemate)

A solution of Intermediate 322A (11 mg, 0.037 mmol) in THF (2 mL) wascooled to −78° C. MeMgBr (3.0 M in Et₂O) (0.122 mL, 0.366 mmol) was thenadded dropwise to this cold solution. After 1 h of vigorous stirring,the reaction mixture was quenched with saturated NH₄Cl and then allowedto thaw to room temperature. Once at room temperature, the mixture wasdiluted with EtOAc, the organic phase was extracted, dried over MgSO₄,filtered, concentrated, and purified by ISCO (12 g, 0-50% EtOAc/Hexanes,16 min. Product at 28%) to afford Intermediate 322B (rac) (6 mg, 0.013mmol, 36.2% yield). LC-MS: Method H, RT=1.57 min, MS (ESI) m/z: 315.9,317.9 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.06 (s, 1H), 4.62 (d,J=1.1 Hz, 1H), 4.27 (ddd, J=10.1, 6.8, 3.2 Hz, 1H), 4.01-3.94 (m, 1H),3.85 (dd, J=9.1, 7.4 Hz, 1H), 2.64 (s, 3H), 2.28 (s, 3H), 1.33 (d, J=6.6Hz, 3H)

Example 322

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 322B with Intermediate I-2 afforded Example 322 (rac) in46% yield following purification by preparative HPLC (Method D, 45-90%over 10 min, 100% for 5 min). LC-MS: Method H, RT=0.98 min, MS (ESI)m/z: 424.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.83 (s,1H), 8.02 (s, 1H), 7.55 (s, 1H), 4.92 (d, J=3.9 Hz, 1H), 4.82 (s, 2H),4.11-4.03 (m, 1H), 4.01-3.93 (m, 1H), 3.92-3.85 (m, 1H), 3.49 (s, 3H),2.77 (s, 3H), 2.71 (s, 3H), 2.29 (s, 3H), 1.25 (d, J=6.1 Hz, 3H).

Example 3233-((2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)butan-2-ol(diastereomeric mixture)

Intermediate 323A:2-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)propanal (racemate)

This example was prepared in a manner analogous to Intermediate 322A.Thus, Intermediate 321A (rac) was reacted to afford Intermediate 323A(rac) (71% yield). LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 214.0,216.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.72 (d, J=2.0 Hz, 1H),6.93 (s, 1H), 4.64 (qd, 2.0 Hz, 1H), 2.66 (s, 3H), 2.33 (s, 3H), 1.55(d, J=6.8 Hz, 3H).

Intermediate 323B:3-((2-bromo-4,5-dimethylbenzo[d]thiazol-6-yl)oxy)butan-2-ol(diastereomeric mixture)

This example was prepared in a manner analogous to Intermediate 322B.Thus, Intermediate 323A (rac) was reacted to afford Intermediate 323B(diastereomeric mixture) (57% yield). LC-MS: Method H, RT=1.40 min, MS(ESI) m/z: 330.0, 332.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.10(s, 1H), 4.36 (qd, J=6.3, 3.4 Hz, 1H), 4.06 (br. s., 1H), 2.64 (s, 3H),2.27 (s, 3H), 1.95 (br. s., 1H), 1.30 (d, J=6.4 Hz, 3H), 1.30-1.25 (m,3H) [Major Diastereomer]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.13 (s, 1H),4.20 (quin, J=6.3 Hz, 1H), 3.97-3.88 (m, 1H), 2.64 (s, 3H), 2.42 (br.s., 1H), 2.27 (s, 3H), 1.30 (d, J=6.4 Hz, 3H), 1.30-1.24 (m, 3H) [MinorDiastereomer].

Example 323

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 323B (diastereomeric mixture) with Intermediate I-2afforded Example 323 (diastereomeric mixture) in 62% yield followingpurification by preparative HPLC (Method D, 50-100% over 40 min). LC-MS:Method H, RT=1.13 min, MS (ESI) m/z: 438.2 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.10 (s, 1H), 8.84 (s, 1H), 8.02 (s, 1H), 7.59 (s, 1H),7.23-6.95 (m, 1H), 4.82 (s, 2H), 4.36 (d, J=5.8 Hz, 1H), 3.81 (d, J=4.4Hz, 1H), 3.49 (s, H), 2.76 (s, 3H), 2.71 (s, 3H), 2.27 (s, 3H), 1.30 (d,J=5.8 Hz, 3H), 1.21 (d, J=6.1 Hz, 3H) [Major Diastereomer]. ¹H NMR (500MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.84 (s, 1H), 8.02 (s, 1H), 7.60 (br. s.,1H), 7.24-6.96 (m, 1H), 4.82 (s, 2H), 4.45 (br. s., 1H), 3.88 (d, J=3.6Hz, 1H), 3.49 (s, 3H), 2.76 (s, 3H), 2.71 (s, 3H), 2.27 (s, 3H), 1.26(d, J=5.5 Hz, 3H), 1.17 (d, J=6.1 Hz, 3H) [Minor Diastereomer].

Example 3242-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-1-morpholinoethanone

Intermediate 324A:2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)acetic acid

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate I-58 with Intermediate I-9 afforded Intermediate 324A in52% yield. LC-MS: Method H, RT=0.79 min, MS (ESI) m/z: 434.0, 436.0(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.60 (s, 1H), 7.86 (s,1H), 7.64 (d, J=7.3 Hz, 1H), 4.38 (br. s., 2H), 4.09 (s, 3H), 2.66 (s,3H).

Example 324

To a suspension of Intermediate 324A (10 mg, 0.023 mmol) in DMF (1 mL)was added N-ethyl-N-isopropylpropan-2-amine (0.024 mL, 0.138 mmol)followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (50% solution in DMF) (0.041 mL, 0.069 mmol). Thereaction mixture was stirred at room temperature for 2 min until all ofstarting material had solvated, then morpholine (5.96 μl, 0.069 mmol)was added. After 15 min, the reaction mixture was filtered and purifiedby preparative HPLC (Method D, 45-85% over 20 min, 100% for 5 min) toafford Example 324 (3.0 mg, 5.96 μmol, 26% yield). LC-MS: Method H,RT=1.14 min, MS (ESI) m/z: 503.1, 505.1 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.74 (s, 1H), 8.62 (s, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.88 (s,1H), 5.13 (s, 2H), 4.10 (s, 3H), 3.69 (br. s., 2H), 3.62 (br. s., 2H),3.49 (br. s., 4H), 2.67 (s, 3H).

Example 325(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)methanol (bis-deuterated)

Intermediate 325A:(2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)methanol(bis-deuterated)

A solution of Intermediate I-54D (50 mg, 0.158 mmol) in toluene (791 μl)and THF (791 μl) was cooled to −78° C. under an atmosphere of N₂. Tothis mixture was added DIBAL-D (0.7 M in toluene) (904 μl, 0.633 mmol).After 30 min of stirring, the solution was allowed to thaw to roomtemperature before being quenched with 3 mL 1 M HCl. The resultingmixture was stirred vigorously for 30 min before being dilute withEtOAc. The organic phase was then extracted, washed with brine, driedover MgSO₄, filtered, concentrated and purified by ISCO (12 g, 0-100%EtOAc/Hexanes, 16 min. Product at 38%) to afford Intermediate 325A (5mg, 0.017 mmol, 10.90% yield) as a white solid. LC-MS: Method H, RT=0.88min, MS (ESI) m/z: 289.7, 291.7 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.14 (s, 1H), 3.88 (s, 3H), 3.35 (s, 1H), 2.33 (s, 3H)

Example 325

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 325A with Intermediate I-2 afforded Example 325 in 61%yield following purification by preparative HPLC (Method D, 30-65% over15 min, 100% for 5 min). LC-MS: Method H, RT=1.06 min, MS (ESI) m/z:397.8 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.85 (d, J=1.7Hz, 1H), 8.03 (s, 1H), 7.69 (s, 1H), 5.02 (s, 1H), 4.82 (s, 2H), 3.92(s, 3H), 3.48 (s, 3H), 2.71 (s, 3H), 2.37 (s, 3H).

Example 3261-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)ethanol

Intermediate 326A:1-(2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)ethanol

A solution of Intermediate I-55 (40 mg, 0.140 mmol) in THF (1398 μl) wascooled to −78° C. MeMgBr (3.0 M in Et₂O) (466 μl, 1.398 mmol) was addeddropwise to this cold mixture. After 30 min, the reaction was quenchedwith saturated NH₄Cl and the resulting mixture was allowed to thaw toroom temperature. Once at room temperature, the mixture was diluted withEtOAc and washed with saturated NH₄Cl followed by brine. The organicphase was dried over MgSO₄, filtered, concentrated and purified by ISCO(12 g, 0-70% EtOAc/Hexanes, 16 min. Product at 20%) to affordIntermediate 326A (12 mg, 0.040 mmol, 28.4% yield). LC-MS: Method H,RT=1.00 min, MS (ESI) m/z: 302.0, 304.0 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.10 (s, 1H), 5.33-5.29 (m, 1H), 3.87 (s, 3H), 2.26 (s,3H), 1.62-1.58 (m, 3H).

Example 326

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 326A with Intermediate I-2 afforded Example 326 in 54%yield following purification by preparative HPLC (Method D, 45-80% over20 min, 100% for 5 min). LC-MS: Method H, RT=1.11 min, MS (ESI) m/z:410.2 (M+H)⁺. ¹H NMR (500 MHz, CHLOROFORM-d) δ 9.09 (s, 1H), 8.71 (s,1H), 7.95 (s, 1H), 7.29 (s, 1H), 6.72 (d, J=10.7 Hz, 1H), 5.49-5.39 (m,1H), 4.85 (s, 2H), 3.94 (s, 3H), 3.74 (s, 1H), 3.58 (s, 3H), 2.71 (s,3H), 2.32 (s, 3H), 1.72 (d, J=6.6 Hz, 3H).

Example 3272-((4-chloro-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-6-yl)oxy)ethanol

Intermediate 327A: 2-bromo-4-chloro-5-methylbenzo[d]thiazol-6-ol

This example was prepared in a manner analogous to Intermediate I-44.Thus, Intermediate I-56 was reacted to afford Intermediate 327A (36%yield) as a light pink solid. LC-MS: Method H, RT=0.94 min, MS (ESI)m/z: 277.7, 279.7, 281.6 (M+H)⁺. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.19(s, 1H), 2.37 (s, 3H).

Intermediate 327B: methyl2((2-bromo-4-chloro-5-methylbenzo[d]thiazol-6-yl)oxy) acetate

This example was prepared in a manner analogous to Intermediate I-49.Thus, Intermediate 327A was reacted to afford Intermediate 327B (79%yield) as an off-white solid. LC-MS: Method H, RT=1.02 min, MS (ESI)m/z: 350.0, 352.0, 353.9 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.01(s, 1H), 4.71 (s, 2H), 3.82 (s, 3H), 2.48 (s, 3H).

Intermediate 327C:2-((2-bromo-4-chloro-5-methylbenzo[d]thiazol-6-yl)oxy)ethanol

This intermediate was prepared in a manner analogous to IntermediateI-51. Thus, Intermediate 327B was reacted to afford Intermediate 327C(82% yield) as an off-white, amorphous solid. LC-MS: Method H, RT=0.93min, MS (ESI) m/z: 321.9, 324.0, 325.9 (M+H)⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.13 (s, 1H), 4.17-4.12 (m, 2H), 4.05 (q, J=4.9 Hz, 2H),2.43 (s, 3H), 1.99 (t, J=6.1 Hz, 1H)

Example 327

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 327C with Intermediate I-2 afforded Example 327 in 49%yield following purification by preparative HPLC (Method D, 45-90% over20 min, 100% for 5 min). LC-MS: Method H, RT=1.10 min, MS (ESI) m/z:430.1, 432.1 (M+H)⁺. ¹H NMR (500 MHz, CHLOROFORM-d) δ 9.07 (s, 1H), 8.95(s, 1H), 7.95 (s, 1H), 7.31 (s, 1H), 4.84 (s, 2H), 4.21 (t, J=4.3 Hz,2H), 4.08 (d, J=3.9 Hz, 2H), 3.58 (s, 3H), 2.71 (s, 3H), 2.49 (s, 3H),2.08-1.98 (m, 1H).

Example 3281-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-5-methylbenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol(racemate)

Intermediate 328A:1-(2-bromo-6-methoxy-5-methylbenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol(racemate)

A solution of Intermediate I-55 (20 mg, 0.070 mmol) in THF (1 mL) wascooled to −78° C. tert-butylmagnesium chloride (0.091 mL, 0.091 mmol)was added. After 30 min, the reaction mixture was warmed to −10° C. andthen quenched with saturated NH₄Cl The resulting mixture was thendiluted with EtOAc, and the organic phase was extracted, dried overMgSO₄, filtered, concentrated and purified by ISCO (12 g, 0-100%EtOAc/Hexanes, 16 min. Product at 16%) to afford Intermediate 328A (rac)(8.5 mg, 0.025 mmol, 35.3% yield). LC-MS: Method H, RT=1.16 min, MS(ESI) m/z: 344.0, 346.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.12(s, 1H), 4.96 (d, J=11.4 Hz, 1H), 3.88 (s, 3H), 2.28 (s, 3H), 0.96 (s,9H).

Example 328

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 328A (rac) with Intermediate I-2 afforded Example 328(rac) in 18% yield following purification by preparative HPLC (Method D,65-100% over 15 min). LC-MS: Method H, RT=1.23 min, MS (ESI) m/z: 452.2(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.64 (s, 1H), 8.07 (s,1H), 7.73 (s, 1H), 6.34 (d, J=10.7 Hz, 1H), 5.00 (d, J=10.7 Hz, 1H),4.83 (br. s., 2H), 3.94 (s, 3H), 3.49 (s, 3H), 2.72 (br. s., 3H), 2.30(s, 3H), 1.00 (br. s., 9H).

Example 3295-fluoro-6-isopropoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 329A: 2-bromo-5-fluoro-6-isopropoxybenzo[d]thiazole

To a solution of Intermediate I-60 (34 mg, 0.137 mmol) in DMF (685 μl)was added 2-iodopropane (68.5 μl, 0.685 mmol) followed by K₂CO₃ (47.4mg, 0.343 mmol). After 3 h of vigorous stirring, the reaction mixturewas diluted with EtOAc, filtered over celite, concentrated and purifiedby ISCO (12 g, 0-10% EtOAc/Hexanes, 16 min. Product at 3%) to affordIntermediate 329A (38 mg, 0.131 mmol, 96% yield) as a white solid.LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 290.1, 292.1 (M+H)⁺. ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.68 (d, J=11.0 Hz, 1H), 7.33 (d, J=7.5 Hz,1H), 4.57 (spt, J=6.1 Hz, 1H), 1.41 (d, J=5.9 Hz, 6H).

Example 329

This example was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 329A with Intermediate I-2 afforded Example 329 in 32%yield following purification by preparative HPLC (Method D, 55-100% over20 min). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 398.3 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.80 (s, 1H), 8.05 (s, 1H), 8.01(d, J=8.0 Hz, 1H), 7.97 (d, J=11.6 Hz, 1H), 4.83 (s, 2H), 4.81-4.73 (m,1H), 3.49 (s, 3H), 2.69 (s, 3H), 1.39 (d, J=6.1 Hz, 6H).

Example 330N-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)benzenesulfonamide

Intermediate 330A:2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl methanesulfonate

To a solution of Example 318 (18 mg, 0.043 mmol) in DCM (1 mL) was addedtriethylamine (0.012 mL, 0.086 mmol) followed by methanesulfonicanhydride (9.71 mg, 0.056 mmol). After 30 min, the reaction mixture wasfurther diluted with DCM and washed with saturated NaHCO₃ followed bybrine. The organic phase was dried over MgSO₄, filtered and concentratedin vacuo to afford Intermediate 330A (18 mg, 0.036 mmol, 84% yield) asan amorphous yellow solid. This material was taken forward withoutfurther purification. LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 498.1,500.1 (M+H)⁺. ¹H NMR (400 MHz, THF) δ 8.68 (d, J=1.5 Hz, 1H), 8.46 (s,1H), 7.69 (dd, J=2.0, 0.9 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 4.55-4.47 (m,2H), 4.39-4.33 (m, 2H), 4.00 (s, 3H), 3.01 (s, 3H), 2.55 (s, 3H).

Example 330

To a solution of Intermediate 330A (8 mg, 0.016 mmol) in DMF (1 mL) wasadded benzenesulfonamide (7.58 mg, 0.048 mmol) followed by K₂CO₃ (11.10mg, 0.080 mmol). The reaction vial was sealed and heated to 100° C. inthe microwave for 30 min. The crude reaction mixture was filtered andpurified by preparative HPLC (Method D, 60-100% over 20 min) to affordExample 330 (1.6 mg, 2.78 μmol, 17% yield). LC-MS: Method H, RT=1.22min, MS (ESI) m/z: 559.1, 561.2 (M+H)⁺. ¹H NMR (500 MHz, CHLOROFORM-d) δ8.73 (br. s., 1H), 8.54 (br. s., 1H), 7.91 (br. s., 2H), 7.77 (br. s.,1H), 7.60-7.47 (m, 3H), 7.25 (br. s., 1H), 5.12 (br. s., 1H), 4.19-4.09(m, 5H), 3.49 (br. s., 2H), 2.67 (br. s., 3H).

Example 3312-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethylpyridin-3-ylcarbamate

To a suspension of Example 318 (75 mg, 0.179 mmol) in THF (3.6 mL) wasadded a solution of phosgene (15% by wt. in toluene) (1.2 mL, 1.790mmol). After 30 min, the resulting chloroformate intermediate wasconcentrated down to a yellow residue. This residue was retaken in THF(3.6 mL) and pyridin-3-amine (50.4 mg, 0.537 mmol) was added followed byHunig's Base (313 μl, 1.79 mmol). After an additional 5 min, thereaction mixture was concentrated, retaken in DMF, filtered and purifiedby preparative HPLC (Method D, 50-100% over 10 min) to afford Example331 (17.9 mg, 0.032 mmol, 18.19% yield) as a yellow solid. LC-MS: MethodH, RT=0.98 min, MS (ESI) m/z: 540.2, 542.2 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 9.99 (br. s., 1H), 8.68 (s, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.19(br. s., 1H), 7.98 (d, J=7.7 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.80 (s,1H), 7.29 (br. s., 1H), 4.48 (d, J=4.2 Hz, 2H), 4.41 (d, J=4.4 Hz, 2H),4.02 (s, 3H), 2.59 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.91.

Preparation of Carbamate Examples

The following carbamates were prepared according to the followinggeneral procedure, which is analogous to Example 331 described above

To a solution of the appropriately substituted Quinoxaline-BenzothiazoleAlcohol (1.0 equiv) in THF (0.05 M) was added a solution of phosgene(15% by wt. in toluene, 10 equiv). The combined solution was stirred atroom temperature for the designated amount of time before theintermediate chloroformate was concentrated in vacuo. This intermediatewas retaken in THF (0.05 M) and the appropriately substitutedaminopyridine, aniline or amine (3.0 equiv) was added. After a minute ofvigorous stirring, an excess of diisopropylethylamine (10 equiv) orpyridine (10 equiv) was added. After an additional 5 min of stirring,the resulting mixture was concentrated, retaken in DMF, filtered andpurified by preparative HPLC to yield the desired example.

LCMS LCMS RT HPLC [M + (Min) Prep H]⁺ Method Method Ex Structure R—OHTime m/z H D NMR 332

318 1 h  570.1, 572.1 1.20 65-100% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ8.76 (br. s., 1H), 8.61 (br. s., 1H), 8.24 (br. s., 1H), 7.97 (br. s.,2H), 7.88 (br. s., 1H), 6.79 (br. s., 1H), 6.59 (br. s., 1H), 4.62- 4.43(m, 2H), 4.33 (br. s., 2H), 4.10 (br. s., 3H), 3.80 (br. s., 3H), 2.75(br. s., 3H). 333

318 1 h  596.2, 598.2 0.87 55-100% 23 min ¹H NMR (500 MHz, DMSO-d₆) δ11.50 (br. s., 1H), 9.87 (br. s., 1H), 8.75 (br. s., 1H), 8.60 (br. s.,1H), 8.05 (br. s., 1H), 7.87 (br. s., 1H), 7.51 (br. s., 1H), 7.17 (br.s., 1H), 7.01 (d, J = 7.7 Hz, 1H), 4.54 (br. s., 2H), 4.48 (br. s., 2H),4.10 (br. s., 3H), 2.67 (br. s., 3H). 334

318 1 h  545.1, 547.1 1.21 55-100% 23 min ¹H NMR (500 MHz, DMSO-d₆) δ8.70 (s, 1H), 8.56 (br. s., 1H), 8.14 (br. s., 1H), 7.97 (d, J = 7.2 Hz,2H), 7.82 (br. s., 1H), 4.56-4.36 (m, 2H), 4.08 (br. s., 2H), 3.83 (br.s, 3H), 2.65 (br. s., 3H). 335

318 1 h  540.2, 542.2 1.19 55-95% 20 min, 100% 5 min ¹H NMR (400 MHz,DMSO-d₆) δ 10.32 (s, 1H), 8.78 (s, 1H), 8.62 (s, 1H), 8.39 (d, J = 6.6Hz, 2H), 8.07 (d, J = 7.3 Hz, 1H), 7.89 (s, 1H), 7.46 (d, J = 6.6 Hz,2H), 4.58 (br. s., 2H), 4.48 (br. s., 2H), 4.15-4.05 (m, 4H), 2.66 (s,3H). 336

318 1 h  554.2, 556.2 1.14 40-80% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 10.23 (br. s., 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.25 (d, J =4.9 Hz, 1H), 8.01 (d, J = 6.7 Hz, 1H), 7.84 (br. s., 1H), 7.31 (br. s.,1H), 7.28 (d, J = 4.9 Hz, 1H), 4.56 (br. s., 2H), 4.47 (br. s., 2H),4.17-4.10 (m, 2H), 4.08 (s, 3H), 2.65 (s, 3H), 2.38 (s, 3H). 337

318 1 h  558.2, 600.2 1.17 50-90% 15 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 10.38 (br. s., 1H), 8.76 (s, 1H), 8.61 (s, 1H), 8.49 (s, 1H),8.23 (s, 1H), 8.06 (d, J = 7.0 Hz, 1H), 7.91-7.81 (m, 2H), 4.58 (br. s.,2H), 4.49 (br. s., 2H), 4.10 (s, 3H), 2.66 (s, 3H). 338

318 1 h  622.1, 624.1 1.16 50-90% 15 min, 100% 5 min 339

I-66 1 h 506.2 0.93 40-90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆)δ 10.07 (br. s., 1H), 8.76 (s, 1H), 8.66 (br. s., 1H), 8.59 (d, J = 1.9Hz, 1H), 8.23 (d, J = 4.1 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 8.00 (d, J= 11.6 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.85 (s, 1H), 7.34 (dd, J =8.4, 4.5 Hz, 1H), 4.58-4.53 (m, 2H), 4.48-4.40 (m, 2H), 4.09 (s, 3H),2.64 (s, 3H). 340

I-66 1 h 524.2 1.16 50-85% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆)δ 10.13 (br. s., 1H), 8.73 (s, 1H), 8.56 (s, 1H), 8.29 (br. s., 1H),8.04 (br. s., 1H), 8.02- 7.96 (m, 2H), 7.82 (s, 1H), 7.15 (dd, J = 8.9,3.2 Hz, 1H), 4.54 (d, J = 4.1 Hz, 2H), 4.45 (d, J = 4.1 Hz, 2H), 4.08(s, 3H), 2.63 (s, 3H). 341

I-66 1 h 536.2 1.15 50-85% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆)δ 8.76 (s, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.24 (br. s., 1H), 8.06-7.96(m, 3H), 7.85 (s, 1H), 7.78 (br. s., 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.51(d, J = 4.7 Hz, 2H), 4.44 (d, J = 4.4 Hz, 2H), 4.09 (s, 3H), 3.80 (s,3H), 2.64 (s, 3H). 342

I-66 1 h 506.2 0.95 40-80% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆)δ 10.31 (s, 1H), 8.75 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.39 (d, J =6.1 Hz, 2H), 8.02 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 11.6 Hz, 1H), 7.84(d, J = 0.8 Hz, 1H), 7.48- 7.44 (m, 2H), 4.59-4.53 (m, 2H), 4.46 (d, J =4.1 Hz, 2H), 4.09 (s, 3H), 2.64 (s, 3H). 343

I-66 1 h 562.2 1.10 45-80% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆)δ 9.87 (br. s., 1H), 8.74 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.04-7.95(m, 2H), 7.87- 7.81 (m, 1H), 7.50 (br. s., 1H), 7.17 (d, J = 8.0 Hz,1H), 7.00 (d, J = 8.5 Hz, 1H), 4.56-4.49 (m, 2H), 4.47-4.39 (m, 2H),4.09 (s, 3H), 2.63 (s, 3H). 344

I-71 16 h  520.2 0.97 35-75% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 10.20 (br. s., 1H), 8.76-8.70 (m, 2H), 8.57 (d, J = 1.7 Hz,1H), 8.30 (d, J = 4.4 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02 (d, J =8.0 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.49(dd, J = 8.5, 5.0 Hz, 1H), 4.91 (td, J = 6.1, 3.2 Hz, 1H), 4.46-4.41 (m,1H), 4.40- 4.34 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.42 (d, J = 6.3Hz, 3H). 345

I-70 16 h  520.2 0.97 50-90% 20 min, 100% 6 min ¹H NMR (500 MHz,DMSO-d₆) δ 10.20 (br. s., 1H), 8.76-8.70 (m, 2H), 8.57 (d, J = 1.7 Hz,1H), 8.30 (d, J = 4.4 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.02 (d, J =8.0 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.49(dd, J = 8.5, 5.0 Hz, 1H), 4.91 (td, J = 6.1, 3.2 Hz, 1H), 4.46-4.41 (m,1H), 4.40- 4.34 (m, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.42 (d, J = 6.3Hz, 3H). 346

I-68 24 h  520.2 0.98 45-100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.98 (br. s., 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.57 (d, J =1.7 Hz, 1H), 8.24-8.18 (m, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.97 (d, J =11.8 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.32(dd, J = 8.3, 4.7 Hz, 1H), 5.27 (td, J = 6.3, 3.2 Hz, 1H), 4.40-4.33 (m,1H), 4.31- 4.25 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.43 (d, J = 6.3Hz, 3H). 347

I-67 24 h  520.2 0.98 45-100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.98 (br. s., 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.57 (d, J =1.7 Hz, 1H), 8.24-8.18 (m, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.97 (d, J =11.8 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.32(dd, J = 8.3, 4.7 Hz, 1H), 5.27 (td, J = 6.3, 3.2 Hz, 1H), 4.40-4.33 (m,1H), 4.31-4.25 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.43 (d, J = 6.3 Hz,3H). 348

I-67 24 h  538.2 1.18 50-100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.73 (s, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.29 (br. s., 1H),8.03 (br. s., 1H), 8.02-7.93 (m, 3H), 7.82 (s, 1H), 7.18-7.10 (m, 1H),5.26 (td, J = 6.3, 3.3 Hz, 1H), 4.40-4.32 (m, 1H), 4.31-4.24 (m, 1H),4.08 (s, 3H), 2.63 (s, 3H), 1.43 (d, J = 6.6 Hz, 3H). 349

I-67 24 h  520.2 0.94 55-95% 22 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.62 (s, 1H), 8.46 (br. s., 3H), 7.94-7.87 (m, 2H), 7.73 (s,1H), 7.62 (br. s., 2H), 5.75-5.75 (m, 1H), 5.32 (d, J = 2.7 Hz, 1H),4.37 (d, J = 8.2 Hz, 1H), 4.32-4.24 (m, 1H), 4.05 (s, 3H), 2.58 (s, 3H),1.46 (d, J = 6.4 Hz, 3H). 350

I-67 24 h  576.2 1.13 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 11.47 (s, 1H), 8.73 (s, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.00(d, J = 8.3 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 7.53- 7.46(m, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 5.24 (td, J= 6.3, 3.4 Hz, 1H), 4.40-4.32 (m, 1H), 4.32-4.25 (m, 1H), 4.08 (s, 3H),2.63 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H). 351

I-67 24 h  545.2 1.21 45-100% 25 min, 100% 10 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.77- 8.72 (m, 2H), 8.58 (d, J = 1.9 Hz, 1H), 8.10 (dd, J =8.5, 2.5 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 11.6 Hz, 1H),7.94 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 1.8, 1.0 Hz, 1H), 5.29 (td, J =6.3, 3.2 Hz, 1H), 4.43-4.35 (m, 1H), 4.33- 4.26 (m, 1H), 4.09 (s, 3H),2.64 (s, 3H), 1.44 (d, J = 6.3 Hz, 3H). 352

I-67 24 h  514.2 1.06 35-75% 20 min, 75% 10 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.66 (s, 1H), 8.50 (s, 1H), 7.94-7.87 (m, 2H), 7.76 (s, 1H),7.33 (br. s., 1H), 7.15 (br. s., 1H), 6.80 (br. s., 1H), 5.06 (br. s.,1H), 4.19 (br. s., 2H), 4.05 (s, 3H), 3.17 (d, J = 5.8 Hz, 2H), 2.59 (s,3H), 2.24 (t, J = 6.9 Hz, 2H), 1.30 (d, J = 6.1 Hz, 3H). 353

I-67 24 h  521.2 1.00 40-80% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 10.53 (s, 1H), 9.21 (d, J = 2.2 Hz, 1H), 8.98 (d, J = 6.1 Hz,1H), 8.59 (d, J = 1.7 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.99 (d, J =11.6 Hz, 1H), 7.85 (s, 1H), 7.76 (dd, J = 5.8, 2.8 Hz, 1H), 5.31 (td, J= 6.3, 3.0 Hz, 1H), 4.43-4.37 (m, 1H), 4.30 (dd, J = 11.0, 6.1 Hz, 1H),4.09 (s, 3H), 2.64 (s, 3H), 1.45 (d, J = 6.3 Hz, 3H). 354

I-67 24 h  559.2 1.07 20-100% 10 min, 100% 5 min 355

I-67 24 h  558.2 1.21 20-100% 10 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.46 (br. s., 1H), 8.65 (s, 1H), 8.49 (s, 1H), 7.95-7.89 (m,2H), 7.75 (s, 1H), 7.68 (br. s., 1H), 7.28 (d, J = 3.0 Hz, 2H), 7.16 (d,J = 7.7 Hz, 1H), 6.34 (br. s., 1H), 5.24 (d, J = 3.4 Hz, 1H), 4.40-4.20(m, 2H), 4.05 (s, 3H), 2.59 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H). 356

I-67 24 h  572.2 1.25 20-100% 10 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.49 (br. s., 1H), 8.65 (s, 1H), 8.50 (s, 1H), 7.98-7.88 (m,2H), 7.76 (s, 1H), 7.68 (br. s., 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.25 (d,J = 2.4 Hz, 1H), 7.22 (br. s., 1H), 6.33 (br. s., 1H), 5.24 (d, J = 3.0Hz, 1H), 4.38-4.19 (m, 2H), 4.05 (s, 3H), 3.74 (s, 2H), 2.59 (s, 3H),1.42 (d, J = 6.4 Hz, 3H). 357

I-67 24 h  535.2 1.14 40-80% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 10.03 (br. s., 1H), 8.73 (br. s., 2H), 8.59 (s, 1H), 8.43(br. s., 1H), 7.86 (d, J = 10.4 Hz, 2H), 7.71 (s, 1H), 5.25 (br. s.,1H), 4.33 (d, J = 8.4 Hz, 1H), 4.24 (dd, J = 10.6, 6.2 Hz, 1H), 4.03 (s,3H), 3.68 (br. s., 3H), 2.56 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H). 358

318 1 h  463.1, 465.1 1.15 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.73 (s, 1H), 8.59 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.86(br. s., 1H), 6.57 (br. s., 2H), 4.36 (d, J = 7.3 Hz, 4H), 4.09 (s, 3H),2.66 (s, 3H). 359

318 1 h  579.2, 581.2 1.09 50-100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.80 (br. s., 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.29 (br. s.,1H), 8.12 (br. s., 1H), 8.02 (d, J = 7.0 Hz, 1H), 7.86 (s, 1H), 7.49(br. s., 1H), 6.46 (br. s., 1H), 4.60 (br. s., 2H), 4.52 (br. s., 2H),4.14 (s, 3H), 2.70 (s, 3H). 360

318 1 h  578.2, 580.2 1.22 50-100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.57 (br. s., 1H), 8.63 (s, 1H), 8.50 (br. s., 1H), 7.92 (d,J = 7.0 Hz, 1H), 7.78 (br. s., 1H), 7.73 (br. s., 1H), 7.40-7.31 (m,2H), 7.21 (br. s., 1H), 6.41 (br. s., 1H), 4.57 (br. s., 2H), 4.48 (br.s., 2H), 4.11 (s, 3H), 2.66 (br. s., 3H). 361

318 1 h  598.2, 600.2 1.18 65-95% 25 min, 95% 10 min ¹H NMR (500 MHz,CHLOROFORM- d) δ 8.67 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 8.08-8.03 (m,1H), 7.71 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 6.95 (br. s., 1H), 4.59(br. s., 2H), 4.34 (br. s., 2H), 4.06 (s, 3H), 3.92 (s, 3H), 2.60 (s,3H). 362

318 1 h  555.2, 557.2 1.16 50-100% 20 min, 100% 5 min ¹H NMR (500 MHz,CHLOROFORM- d) δ 8.74-8.61 (m, 3H), 8.47 (s, 1H), 7.71 (s, 1H), 7.34 (d,J = 7.2 Hz, 1H), 6.66 (br. s., 1H), 4.61-4.52 (m, 2H), 4.35-4.31 (m,2H), 4.06 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H). 363

318 1 h  577.2, 579.2 1.19 50-100% 20 min, 100% 5 min ¹H NMR (500 MHz,CHLOROFORM- d) δ 8.76 (br. s., 1H), 8.57 (br. s., 1H), 7.80 (br. s.,1H), 7.63 (br. s., 1H), 7.44 (br. s., 1H), 4.67 (br. s., 2H), 4.43 (br.s., 2H), 4.16 (br. s., 6H), 2.69 (br. s., 3H). 364

318 1 h  529.2, 531.2 1.16 50-80% 25 min, 100% 7 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.61 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 7.92 (d, J = 7.6Hz, 1H), 7.80 (s, 1H), 7.60 (br. s., 2H), 4.55 (br. s., 2H), 4.46 (br.s., 2H), 4.11 (s, 3H), 2.67 (s, 3H). 365

318 1 h  543.2, 545.2 1.21 50-90% 25 min, 100% 10 min ¹H NMR (500 MHz,CD₂Cl₂) δ 8.65 (br. s., 1H), 8.46 (br. s., 1H), 7.70 (br. s., 1H), 7.51(br. s., 1H), 7.36 (d, J = 5.8 Hz, 1H), 7.27 (br. s., 1H), 6.49 (br. s.,1H), 4.50 (br. s., 2H), 4.30 (br. s., 2H), 4.05 (br. s., 3H), 3.76 (br.s., 3H), 2.59 (br. s., 3H). 366

318 1 h  545.1, 547.1 1.12 60-90% 22 min, 100% 7 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.62 (s, 1H), 8.49 (br. s., 1H), 7.92 (s, 1H), 7.86 (d, J =7.9 Hz, 1H), 7.77 (br. s., 1H), 4.49 (br. s., 2H), 4.38 (br. s., 2H),4.04 (s, 3H), 2.88 (s, 3H), 2.72 (s, 3H). 367

318 1 h  607.2, 609.2 1.19 60-100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.67 (br. s., 1H), 8.60 (s, 1H), 8.47 (br. s., 1H), 8.15 (br.s., 1H), 7.90 (br. s., 2H), 7.75 (br. s., 1H), 6.15 (br. s., 1H), 4.51(br. s., 2H), 4.43 (br. s., 2H), 4.04 (s, 3H), 3.51 (s, 3H), 2.60 (s,3H), 2.38 (br. s., 3H). 368

318 1 h  554.2, 556.2 1.02 50-95% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.69 (s, 1H), 8.55 (s, 1H), 8.46 (br. s., 1H), 8.43 (br. s.,1H), 7.93 (br. s., 2H), 7.82 (s, 1H), 7.64 (br. s., 1H), 7.33 (br. s.,1H), 4.38 (d, J = 9.8 Hz, 4H), 4.22 (d, J = 5.8 Hz, 2H), 4.06 (s, 3H),2.63 (s, 3H). 369

318 1 h  554.2, 556.2 1.01 50-100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.72 (br. s., 1H), 8.60-8.51 (m, 3H), 8.11- 7.88 (m, 2H),7.85 (br. s., 1H), 7.32 (d, J = 4.6 Hz, 2H), 4.47 (d, J = 15.9 Hz, 4H),4.30 (d, J = 6.1 Hz, 2H), 4.13 (s, 3H), 2.69 (s, 3H). 370

I-69 24 h   575.4, 577.4 1.19 60-100% 20 min, 100% 5 min ¹H NMR (500MHz, DMSO-d₆) δ 8.71 (br. s., 1H), 8.56 (br. s., 1H), 7.99 (d, J = 7.02Hz, 1H), 7.83 (br. s., 1H), 5.33 (br. s., 1H), 4.41 (d, J = 10.68 Hz,1H), 4.30 (br. s., 1H), 4.09 (br. s., 3H), 1.43 (d, J = 5.49 Hz, 3H).371

I-69 24 h   579.4, 581.4 1.22 70-100% 20 min, 100% 5 min ¹H NMR (500MHz, DMSO-d₆) δ 8.73 (br. s., 1H), 8.63 (br. s., 1H), 8.48 (br. s., 1H),8.08 (d, J = 8.55 Hz, 1H), 7.86-8.00 (m, 3H), 7.76 (br. s., 1H), 5.30(br. s., 1H), 4.22-4.46 (m, 2H), 4.06 (br. s., 3H), 2.62 (br. s., 3H),1.44 (d, J = 4.88 Hz, 3H). 372

I-69 24 h   554.1, 556.1 1.24 60-100% 13 min, 100% 5 min ¹H NMR (500MHz, DMSO-d₆) δ 9.97 (br. s., 1H), 8.65 (br. s., 2H), 8.50 (br. s., 1H),8.21 (br. s., 1H), 7.86-8.00 (m, 2H), 7.78 (br. s., 1H), 7.33 (br. s.,1H), 5.28 (br. s., 1H), 4.24-4.45 (m, 2H), 4.07 (s, 3H), 2.62 (s, 3H),1.43 (d, J = 5.80 Hz, 3H). 373

I-69 24 h   611.1, 613.1 1.20 65-100% 13 min, 100% 5 min ¹H NMR (500MHz, DMSO-d₆) δ 9.63- 9.76 (m, 1H), 8.74 (s, 1H), 8.59 (s, 1H),7.98-8.05 (m, 1H), 7.85 (s, 1H), 7.71- 7.79 (m, 1H), 7.36-7.49 (m, 1H),7.05- 7.17 (m, 1H), 6.89-6.97 (m, 1H), 4.99- 5.34 (m, 1H), 4.23-4.43 (m,2H), 4.08 (s, 3H), 3.08-3.19 (m, 1H), 2.64 (s, 3H), 1.40 (d, J = 6.10Hz, 3H). 374

I-69 24 h   622.2, 624.2 1.36 60-100% 20 min, 100% 5 min ¹H NMR (500MHz, DMSO-d₆) δ 10.39 (br. s., 1H), 8.76 (s, 1H), 8.68 (s, 1H), 8.54 (s,1H), 8.12 (d, J = 8.55 Hz, 1H), 7.98 (d, J = 7.63 Hz, 1H), 7.74-7.87 (m,2H), 5.29 (br. s., 1H), 4.22-4.47 (m, 2H), 4.07 (s, 3H), 2.62 (s, 3H),1.43 (d, J = 6.41 Hz, 3H). 375

I-69 24 h   593.2, 595.2 1.15 55-85% 16 min, 100% 7 min ¹H NMR (500 MHz,DMSO-d₆) δ 11.43 (br. s., 1H), 9.42-9.72 (m, 1H), 8.59 (s, 1H), 8.46 (s,1H), 8.19 (br. s., 1H), 8.02 (br. s., 1H), 7.84-7.94 (m, 1H), 7.74 (s,1H), 7.39 (br. s., 1H), 6.37 (br. s., 1H), 5.24 (d, J = 3.36 Hz, 1H),4.19-4.40 (m, 2H), 4.04 (s, 3H), 2.59 (s, 3H), 1.40 (d, J = 6.41 Hz,3H). 376

I-69 24 h   568.2, 570.2 1.06 40-100% 20 min, 100% 5 min ¹H NMR (500MHz, DMSO-d₆) δ 9.46 (br. s., 1H), 8.66 (br. s., 1H), 8.54 (s, 1H), 8.40(s, 1H), 8.30 (d, J = 4.58 Hz, 1H), 7.84 (d, J = 7.63 Hz, 1H), 7.68 (s,1H), 7.48 (d, J = 5.19 Hz, 1H), 5.22 (dd, J = 3.05, 6.10 Hz, 1H),4.14-4.41 (m, 2H), 3.99 (s, 3H), 2.54 (s, 3H), 2.13-2.33 (m, 3H), 1.37(d, J = 6.41 Hz, 3H). 377

I-69 24 h   568.2, 570.2 1.07 60-100% 20 min, 100% 5 min ¹H NMR (500MHz, DMSO-d₆) δ 9.80 (br. s., 1H), 8.11-8.68 (m, 3H), 7.59- 7.89 (m,3H), 7.15 (d, J = 8.24 Hz, 1H), 5.23 (br. s., 1H), 4.20-4.48 (m, 2H),4.02 (s, 3H), 2.57 (s, 3H), 2.36 (s, 3H), 1.40 (d, J = 6.41 Hz, 3H). 378

318 1 h  600.2, 602.2 1.28 50-85% 20 min, 100% 7 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.48- 9.57 (m, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 7.90-8.00 (m,1H), 7.80 (s, 1H), 6.95- 7.11 (m, 1H), 6.52-6.68 (m, 1H), 4.25- 4.47 (m,4H), 4.03 (s, 3H), 3.64 (br. s., 2H), 3.34-3.45 (m, 6H), 2.59 (s, 3H).

Example 3791-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-isobutoxypropan-2-ylpyridin-3-ylcarbamate

Intermediate 379A:1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-isobutoxypropan-2-ol

To a suspension of Intermediate I-64 (15 mg, 0.044 mmol) in THF (1 mL)was added tetrabutylammonium bromide (28.3 mg, 0.088 mmol) followed by a0.33 M solution of KOH (0.20 mL, 0.066 mmol). 2-(isobutoxymethyl)oxirane(0.1 mL) was then added, and the resulting mixture was heated to 65° C.in a sealed tube. After 16 h, the reaction was quenched with saturatedNH₄Cl and diluted with EtOAc. The organic phase was washed with brine,dried over MgSO₄, filtered, concentrated and purified by ISCO (4 g,0-60% EtOAc/Hexanes, 16 min. Product at 25%) to afford Intermediate 379A(14 mg, 0.024 mmol, 54.1% yield) as a yellow solid. LC-MS: Method H,RT=1.23 min, MS (ESI) m/z: 472.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d)δ 8.60 (d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.81 (d, J=11.4 Hz, 1H), 7.75(d, J=0.9 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 4.30-4.22 (m, 1H), 4.22-4.15(m, 2H), 4.13 (s, 3H), 3.70-3.61 (m, 2H), 3.32-3.25 (m, 2H), 2.65 (s,3H), 2.62 (d, J=4.8 Hz, 1H), 1.97-1.80 (m, 1H), 0.92 (d, J=6.8 Hz, 6H).

Example 379

This example was prepared according to the general procedure forcarbamates described in the table above. Thus, reaction of Intermediate379A with 3-aminopyridine afforded Example 379 in 77% yield followingpurification by preparative HPLC (Method D, 45-100% over 15 min). LC-MS:Method H, RT=1.03 min, MS (ESI) m/z: 592.3 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 10.37 (br. s., 1H), 8.79 (br. s., 1H), 8.72 (s, 1H), 8.56 (s,1H), 8.36 (d, J=4.3 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 8.02 (d, J=8.2 Hz,1H), 7.97 (d, J=11.6 Hz, 1H), 7.82 (s, 1H), 7.61-7.53 (m, 1H), 5.42-5.32(m, 1H), 4.53-4.45 (m, 1H), 4.45-4.37 (m, 1H), 4.09 (s, 3H), 3.80 (d,J=5.2 Hz, 2H), 3.37-3.29 (m, 1H), 3.28-3.22 (m, 1H), 2.63 (s, 3H), 1.84(dt, J=13.2, 6.7 Hz, 1H), 0.93-0.81 (m, 6H).

Example 3801-(benzyloxy)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ylpyridin-3-ylcarbamate

Intermediate 380A:1-(benzyloxy)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol

To a suspension of Intermediate I-64 (15 mg, 0.044 mmol) in THF (1 mL)was added tetrabutylammonium bromide (28.3 mg, 0.088 mmol) followed by a0.33 M solution of KOH (0.20 mL, 0.066 mmol).2-((benzyloxy)methyl)oxirane (72.2 mg, 0.439 mmol) was then added, andthe resulting mixture was heated to 65° C. in a sealed tube. After 16 h,the reaction was quenched with saturated NH₄Cl and diluted with EtOAc.The organic phase was washed with brine, dried over MgSO₄, filtered,concentrated and purified by ISCO (4 g, 0-60% EtOAc/Hexanes, 16 min.Product at 35%) to afford Intermediate 380A (16 mg, 0.032 mmol, 72.0%yield) as a yellow solid. LC-MS: Method H, RT=1.21 min, MS (ESI) m/z:506.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.60 (d, J=2.0 Hz, 1H),8.53 (s, 1H), 7.80 (d, J=11.2 Hz, 1H), 7.74 (dd, J=1.8, 0.9 Hz, 1H),7.46 (d, J=7.7 Hz, 1H), 7.38-7.27 (m, 5H), 4.61 (s, 2H), 4.33-4.24 (m,1H), 4.23-4.17 (m, 2H), 4.12 (s, 3H), 3.77-3.68 (m, 2H), 2.66-2.62 (m,4H).

Example 380

Example 380 was prepared according to the general procedure forcarbamates described in the table above. Thus, reaction of Intermediate380A with 3-aminopyridine afforded Example 380 in 34% yield followingpurification by preparative HPLC (Method D, 45-100% over 18 min). LC-MS:Method H, RT=1.02 min, MS (ESI) m/z: 626.3 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 10.28 (br. s., 1H), 8.74 (br. s., 2H), 8.58 (br. s., 1H),8.31 (br. s., 1H), 8.07-7.95 (m, 3H), 7.85 (br. s., 1H), 7.50 (br. s.,1H), 7.39-7.27 (m, 5H), 5.41 (br. s., 1H), 4.60 (d, J=7.3 Hz, 2H), 4.47(d, J=17.4 Hz, 2H), 4.09 (br. s., 3H), 3.86 (br. s., 2H), 2.64 (br. s.,3H).

Example 3812-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl(6-methoxypyridin-3-yl)carbamate (racemate)

Intermediate 381A: methyl2((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy) propanoate(racemate)

Intermediate 381A was prepared in a manner analogous to IntermediateI-50. Thus, Intermediate I-44 was reacted to afford Intermediate 381A(rac) (46% yield) as a white solid. LC-MS: Method H, RT=1.12 min, MS(ESI) m/z: 368.0, 370.0, 372.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.23 (d, J=6.8 Hz, 1H), 4.81 (q, J=6.8 Hz, 1H), 3.78 (s, 3H), 1.71 (d,J=6.8 Hz, 3H).

Intermediate 381B:2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-1-ol(racemate)

Intermediate 381B was prepared in a manner analogous to IntermediateI-51. Thus, Intermediate 381A (rac) was reacted to afford Intermediate381B (rac) (75% yield) as an off-white, amorphous solid. LC-MS: MethodH, RT=1.05 min, MS (ESI) m/z: 339.9, 341.9, 343.9 (M+H)⁺. ¹H NMR (400MHz, METHANOL-d₄) δ 7.71 (d, J=7.3 Hz, 1H), 4.64-4.52 (m, 1H), 3.79-3.67(m, 2H), 1.34 (d, J=6.2 Hz, 3H)

Intermediate 381C:2-((2-bromo-4-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propyl(6-methoxypyridin-3-yl)carbamate (racemate)

Intermediate 381C was prepared according to the general procedure forcarbamates described in the table above. Thus, reaction of Intermediate381B (rac) with 3-amino-6-methoxypyridine afforded Intermediate 381C(rac) in 90% yield. LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 489.9,491.9, 493.9 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.05 (br. s., 1H),7.73 (br. s., 1H), 7.35 (d, J=7.3 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.53(br. s., 1H), 4.76-4.59 (m, 1H), 4.36 (d, J=5.3 Hz, 2H), 3.91 (s, 3H),1.43 (d, J=6.4 Hz, 3H).

Example 381

Example 381 was prepared according to the general procedure forquinoxaline-benzothiazoles described in the table above. Thus, reactionof Intermediate 381C (rac) with Intermediate I-9 afforded Example 381(rac) in 23% yield following purification by preparative HPLC (Method D,55-95% over 30 min). LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 584.1,586.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.71 (br. s., 1H), 8.73 (s,1H), 8.58 (d, J=1.4 Hz, 1H), 8.21 (br. s., 1H), 8.07 (d, J=7.4 Hz, 1H),7.85 (s, 1H), 7.77 (br. s., 1H), 6.77 (d, J=8.3 Hz, 1H), 4.92 (td,J=6.2, 3.3 Hz, 1H), 4.46-4.27 (m, 2H), 4.10 (s, 3H), 3.78 (s, 3H), 2.66(s, 3H), 1.43 (d, J=6.3 Hz, 3H)

Example 382(S)-2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propyl(6-methoxypyridin-3-yl)carbamate

This example was prepared by subjecting Example 381 (rac) to chiral,super-critical fluid chromatography conditions (Berger Multigram II SFC,Chiralpak OJ, 21×250 mm, 5 micron, 45% EtOH/−0.1% DEA/55% CO₂, 40 mL/minflow rate) to give Example 382 as the second eluting enantiomer. Theabsolute stereochemistry of this example was assigned by analogy toother biologically active enantiomers in the same series. LC-MS: MethodH, RT=1.31 min, MS (ESI) m/z: 584.1, 586.1 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.71 (br. s., 1H), 8.73 (s, 1H), 8.58 (d, J=1.4 Hz, 1H), 8.21(br. s., 1H), 8.07 (d, J=7.4 Hz, 1H), 7.85 (s, 1H), 7.77 (br. s., 1H),6.77 (d, J=8.3 Hz, 1H), 4.92 (td, J=6.2, 3.3 Hz, 1H), 4.46-4.27 (m, 2H),4.10 (s, 3H), 3.78 (s, 3H), 2.66 (s, 3H), 1.43 (d, J=6.3 Hz, 3H).

Example 3832-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl(2-chlorothiazol-4-yl)carbamate

To a suspension of Example 318 (12 mg, 0.029 mmol) and2-chlorothiazole-4-carboxylic acid (9.35 mg, 0.057 mmol) in Toluene (1mL) was added triethylamine (7.97 μl, 0.057 mmol) followed bydiphenylphosphoryl azide (15.73 mg, 0.057 mmol). The reaction vessel wasthen sealed and heated to 110° C. for 3 hours. The resulting mixture wascooled to room temperature, concentrated and purified by preparativeHPLC (Method D, 60-100% over 20 min, hold at 100% for 10 min) to affordExample 383 in 20% yield. LC-MS: Method H, RT=1.35 min, MS (ESI) m/z:580.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.71 (br. s., 1H), 8.73 (s,1H), 8.58 (d, J=1.4 Hz, 1H), 8.21 (br. s., 1H), 8.07 (d, J=7.4 Hz, 1H),7.85 (s, 1H), 7.77 (br. s., 1H), 6.77 (d, J=8.3 Hz, 1H), 4.92 (td,J=6.2, 3.3 Hz, 1H), 4.46-4.27 (m, 2H), 4.10 (s, 3H), 3.78 (s, 3H), 2.66(s, 3H), 1.43 (d, J=6.3 Hz, 3H).

Example 3842-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethylthiazol-5-ylcarbamate

Example 384 was prepared in a manner analogous to Example 383. Thus,Example 318 was reacted with thiazole-5-carboxylic acid to affordExample 384 (3% yield) following purification by preparative HPLC(Method D, 40-80% over 20 min, hold at 100% for 5 min). LC-MS: Method H,RT=1.21 min, MS (ESI) m/z: 546.1, 548.1 (M+H)⁺. ¹H NMR (500 MHz,CHLOROFORM-d) δ 8.66-8.85 (m, 1H), 8.53-8.62 (m, 1H), 8.38-8.51 (m, 1H),7.71-7.85 (m, 1H), 7.53-7.64 (m, 1H), 7.36-7.45 (m, 1H), 7.28-7.33 (m,1H), 4.67 (br. s., 2H), 4.41 (br. s., 2H), 4.14 (br. s., 3H), 2.68 (br.s., 3H).

Example 385(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl(6-(hydroxymethyl)pyridin-3-yl)carbamate

Intermediate 385A: (5-aminopyridin-2-yl)methanol

To a suspension of methyl 5-aminopicolinate (70 mg, 0.460 mmol) in THF(3 mL) was added a solution of LAH (1 M in THF) (0.920 mL, 0.920 mmol)at 0° C. The mixture was allowed to warm to room temperature and stirredovernight. After 16 h, the reaction was quenched with water (0.1 mL) at0° C. A solution of sodium hydroxide (2 N, 0.1 mL) was subsequentlyadded followed by an additional quantity of water (0.3 mL). Magnesiumsulfate was added and the mixture was stirred for 1 hour before beingfiltered over a pad of celite and washed with THF. The filtrate wasconcentrated in vacuo to afford Intermediate 385A (35 mg, 0.282 mmol,61.3% yield) as a yellow solid. This material was taken on withoutfurther purification. LC-MS: Method H, RT=0.44 min, MS (ESI) m/z: 125.1(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.80-7.88 (m, 1H), 7.05-7.16 (m,1H), 6.83-6.96 (m, 1H), 4.88-5.04 (m, 1H), 4.27-4.41 (m, 2H).

Intermediate 385B:6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-amine

To a stirred solution of crude Intermediate 385A (225 mg, 1.812 mmol) inDMF (5 mL) was added TBDMS-Cl (410 mg, 2.72 mmol) followed by imidazole(222 mg, 3.26 mmol). The reaction mixture was stirred for 1 h at roomtemperature before being concentrated and purified by ISCO (24 g, 0-100%EtOAc/Hexanes, 15 min. Product at 65%) to afford Intermediate 385B (132mg, 0.554 mmol, 30.5% yield), as a yellow solid. LC-MS: Method H,RT=0.81 min, MS (ESI) m/z: 239.4 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ7.79 (d, J=2.64 Hz, 1H), 7.00 (s, 1H), 6.77-6.91 (m, 1H), 5.13 (s, 2H),4.50 (s, 2H), 0.84 (s, 9H), 0.00 (s, 6H).

Intermediate 385C:(R)-1-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)carbamate

This intermediate was prepared according to the general procedure forcarbamates described in the table above. Thus, reaction of IntermediateI-69 with Intermediate 385B afforded Intermediate 385C, which wastelescoped into the subsequent silyl-deprotection reaction. LC-MS:Method H, RT=1.26 min, MS (ESI) m/z: 698.5, 700.5 (M+H)⁺.

Example 385

Intermediate 385C was concentrated and redissolved in 10 mL mixture ofMeOH (9.5 mL) and 12 M HCl (0.5 mL). The resulting solution was stirredfor 10 minutes before being concentrated down and purified bypreparative HPLC (Method D, 50-100% over 10 min, hold at 100% for 10min) to afford Example 385 in 9% overall yield as a yellow solid. LC-MS:Method H, RT=1.07 min, MS (ESI) m/z: 584.3, 586.3 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 9.69-9.99 (m, 1H), 8.77 (s, 1H), 8.60-8.65 (m, 1H),8.53-8.57 (m, 1H), 8.02-8.10 (m, 1H), 7.82-7.93 (m, 2H), 7.33-7.42 (m,1H), 5.21-5.37 (m, 2H), 4.46-4.52 (m, 2H), 4.38-4.45 (m, 1H), 4.24-4.35(m, 1H), 2.67 (s, 4H), 1.43 (d, J=6.38 Hz, 3H).

Example 386(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Example 386 was prepared according to the general procedure forcarbamates described in the table above. Thus, reaction of IntermediateI-72 with 2-methylpyrimidin-5-amine and pyridine afforded Example 386 in46% yield following purification by Prep HPLC (Method D, 50-100% over 10min, hold 100% for 8 min). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z:549.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.74 (s, 2H), 8.63 (d,J=1.5 Hz, 1H), 8.57 (s, 1H), 7.85 (d, J=11.4 Hz, 1H), 7.79 (s, 1H),7.58-7.52 (m, 1H), 6.51 (br. s., 1H), 5.18 (dd, J=6.5, 3.0 Hz, 1H),4.69-4.59 (m, 1H), 4.16 (s, 3H), 2.70 (s, 3H), 2.68 (s, 3H), 1.50 (d,J=6.6 Hz, 3H), 1.46 (d, J=6.4 Hz, 3H).

Example 387(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(6-(2-hydroxyethyl)pyridin-3-yl)carbamate

Example 387 was prepared according to the general procedure forcarbamates described in the table above. Thus, reaction of IntermediateI-72 with 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-amineafforded the TBS-protected intermediate of the desired product. Thecrude reaction mixture was concentrated and retaken in a 20:1 mixture ofMeOH/concentrated HCl to affect the desired silyl deprotection andafford Example 387 in 46% yield following purification by Prep HPLC(Method D, 50-100% over 10 min, hold 100% for 8 min). LC-MS: Method H,RT=0.98 min, MS (ESI) m/z: 578.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d)δ 9.79 (br. s., 1H), 8.73 (s, 1H), 8.58 (d, J=1.8 Hz, 1H), 8.53 (br. s.,1H), 8.04 (d, J=8.4 Hz, 1H), 7.96 (d, J=11.7 Hz, 1H), 7.83 (s, 1H), 7.78(d, J=7.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 5.10 (qd, J=6.5, 2.9 Hz, 1H),4.82-4.73 (m, 1H), 4.08 (s, 3H), 3.67 (t, J=6.9 Hz, 2H), 2.79 (t, J=6.8Hz, 2H), 2.63 (s, 3H), 1.39 (m, 6H)

Example 388(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(2-hydroxyethoxy)pyridin-4-yl)carbamate

Example 388 was prepared according to the general procedure forcarbamates described in the table above. Thus, reaction of IntermediateI-72 with 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-4-amineafforded the TBS-protected intermediate of the desired product. ExcessTBAF (10 equiv, 1 M in THF) was added to the crude reaction mixture toafford Example 388 in 26% yield following purification by Prep HPLC(Method D, 50-100% over 10 min, hold 100% for 8 min). LC-MS: Method H,RT=1.06 min, MS (ESI) m/z: 594.2 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d)δ 9.99 (s, 1H), 8.67 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 7.97 (d, J=8.1 Hz,1H), 7.89 (d, J=11.7 Hz, 1H), 7.86 (d, J=5.9 Hz, 1H), 7.77 (s, 1H), 6.96(dd, J=5.7, 1.8 Hz, 1H), 6.83 (d, J=1.3 Hz, 1H), 5.10-5.00 (m, 1H),4.76-4.67 (m, 2H), 4.12 (t, J=5.1 Hz, 2H), 4.01 (s, 3H), 3.58 (q, J=5.4Hz, 2H), 2.56 (s, 3H), 1.32 (m, 6H).

Example 389(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

To a solution of Intermediate I-73 (30 mg, 0.051 mmol) in THF (1.5 mL)was added ethanol (0.5 mL, 8.56 mmol) followed by sodium hydride (20.53mg, 0.513 mmol, 60% suspension in mineral oil). The reaction mixture wasstirred for 10 min at room temperature before being quenched withsaturated NH₄Cl (˜0.15 mL). The resulting mixture was diluted withEtOAc, filtered over celite, concentrated, retaken in DMF, filtered andpurified by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for 8min) to afford Example 389 (17.7 mg, 0.030 mmol, 58% yield) as a yellowsolid. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 563.2 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 9.96 (br. s., 1H), 8.71 (br. s., 2H), 8.63 (s, 1H),8.50 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.91 (d, J=11.3 Hz, 1H), 7.75 (s,1H), 5.10 (dd, J=6.7, 2.4 Hz, 1H), 4.78 (d, J=4.0 Hz, 1H), 4.49 (q,J=7.0 Hz, 2H), 2.59 (s, 3H), 2.50 (s, 3H-buried under d-DMSO), 1.42 (t,J=7.2 Hz, 3H), 1.38 (m, 6H).

Example 390(2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylamino)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

To a vial charged with Intermediate I-73(10 mg, 0.017 mmol) was addedmethanamine (33% solution in EtOH) (1 mL, 8.00 mmol). The mixture wasstirred at room temperature for 16 h before being concentrated andpurified by Prep HPLC (Method D, 50-100% over 10 min, hold 100% for 8min) to afford Example 390 (17.7 mg, 0.030 mmol, 58% yield) as a yellowsolid. LC-MS: Method H, RT=0.92 min, MS (ESI) m/z: 548.1 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 9.97 (br. s., 1H), 8.72 (br. s., 2H), 8.42 (s, 1H),8.27 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.92 (d, J=11.3 Hz, 1H), 7.56 (s,1H), 5.10 (d, J=4.9 Hz, 1H), 4.79 (d, J=4.0 Hz, 1H), 2.96 (s, 3H), 2.50(s, 3H-buried under d-DMSO), 1.38 (m, 6H).

Example 391(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(6-carbamoylpyridin-3-yl)carbamate

To a vial charged with Intermediate I-74 (20 mg, 0.034 mmol) was addedammonia (7M solution in MeOH) (1 mL, 14.00 mmol). The mixture was sealedand heated to 65° C. for 24 h before being concentrated and purified byPrep HPLC (Method D, 50-100% over 10 min, hold 100% for 8 min) to affordExample 391 (8 mg, 0.013 mmol, 38% yield) as a yellow solid. LC-MS:Method H, RT=1.21 min, MS (ESI) m/z: 577.2 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 10.18 (br. s., 1H), 8.71-8.61 (m, 2H), 8.52 (s, 1H), 8.01 (d,J=8.2 Hz, 2H), 7.98-7.89 (m, 3H), 7.79 (s, 1H), 7.45 (br. s., 1H), 5.12(d, J=5.8 Hz, 1H), 4.80 (d, J=6.1 Hz, 1H), 4.05 (s, 3H), 2.60 (s, 3H),1.39 (m, 6H).

Example 392(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(6-((2-hydroxyethyl)carbamoyl)pyridin-3-yl)carbamate

To a solution of Intermediate I-74 (10 mg, 0.017 mmol) in THF (1 mL) wasadded ethanolamine (0.1 mL). The reaction mixture was allowed to stir atroom temperature for 16 h before being concentrated and purified by PrepHPLC (Method D, 50-100% over 10 min, hold 100% for 8 min) to affordExample 392 (8.7 mg, 0.014 mmol, 81% yield) as a yellow solid. LC-MS:Method H, RT=1.15 min, MS (ESI) m/z: 621.1 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 10.15 (br. s., 1H), 8.63 (d, J=5.8 Hz, 2H), 8.53-8.43 (m,2H), 7.97 (d, J=8.5 Hz, 2H), 7.94-7.86 (m, 2H), 7.76 (s, 1H), 5.11 (d,J=5.8 Hz, 1H), 4.89-4.84 (m, 1H), 4.81 (br. s., 1H), 4.04 (s, 3H), 3.48(d, J=5.5 Hz, 2H), 3.32 (d, J=5.5 Hz, 2H), 2.58 (s, 3H), 1.38 (m, 6H).

Example 393(2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

To a solution of Intermediate I-75 (13 mg, 0.022 mmol) in THF (1 mL) wasadded methanamine (33% solution in EtOH) (0.2 mL, 1.60 mmol). Thereaction mixture was allowed to stir at room temperature for 16 h beforebeing concentrated and purified by Prep HPLC (Method D, 50-100% over 10min, hold 100% for 8 min) to afford Example 393 (5 mg, 0.008 mmol, 37%yield) as a yellow solid. LC-MS: Method H, RT=0.99 min, MS (ESI) m/z:576.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.48 (s, 1H), 9.07 (d, J=4.9Hz, 1H), 8.83 (s, 1H), 8.73 (br. s., 2H), 8.11-8.01 (m, 2H), 7.94 (d,J=11.6 Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.83 (d, J=4.3 Hz, 1H),2.98-2.90 (m, 3H), 2.70 (s, 3H), 2.52 (br. s., 3H), 1.40 (m, 6H).

Preparation of Carbamate Examples

The Carbamates in the table below were prepared according to thefollowing general procedure, which is analogous to Intermediate I-82described above

To a solution of the appropriately substituted quinoxaline-benzothiazolealcohol (1.0 equiv) in THF (0.05 M) was added a solution of phosgene(15% by wt. in toluene, 10 equiv). This solution was stirred at roomtemperature overnight, and the intermediate chloroformate wasconcentrated in vacuo. This crude chloroformate was then retaken in THF(0.05 M) and added dropwise to a pre-mixed solution of pyridine (10equiv) and the appropriately substituted amino-heterocycle or amine (3.0equiv) in either THF (0.05 M) or DCM (0.05) (whichever gave the bestreagent solubility). After 10 min of stirring, the combined mixture wasconcentrated and purified by preparative HPLC to yield the desiredexample.

LCMS LCMS RT HPLC [M + (Min) Prep Ex. H]⁺ Method Method No. StructureR—OH m/z H D NMR 394

I-67 568.3 1.13 30- 65% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ8.74 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 7.99-7.94 (m, 2H), 7.83 (s, 1H),7.14 (t, J = 5.5 Hz, 1H), 5.13-5.04 (m, 1H), 4.27- 4.16 (m, 2H), 4.09(s, 3H), 3.31-3.16 (m, 6H), 2.63 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H),1.88-1.78 (m, 2H), 1.73 (quin, J = 6.7 Hz, 2H), 1.32 (d, J = 6.6 Hz, 3H)395

318 565.2, 567.3 1.22 60- 100% 20 min, 100% 8 min — 396

318 545.2, 556.2 1.02 50- 100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.67 (s, 1H), 8.53 (br. s., 1H), 8.46 (br. s., 1H), 7.92 (br.s., 1H), 7.88 (d, J = 6.4 Hz, 1H), 7.81 (br. s., 1H), 7.73 (t, J = 7.2Hz, 1H), 7.38-7.30 (m, 1H), 7.29-7.21 (m, 1H), 4.39 (d, J = 1.6 Hz, 4H),4.28 (d, J = 5.8 Hz, 2H), 4.05 (s, 3H), 2.62 (s, 3H) 397

318 557.2, 559.3 1.21 45- 90% 30 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.59 (s, 1H), 8.45 (br. s., 1H), 7.85-7.81 (m, 1H), 7.72 (br.s., 1H), 7.51 (br. s., 1H), 7.40 (s, 1H), 6.82 (s, 1H), 4.31 (d, J = 8.2Hz, 4H), 4.00 (m, 5H), 3.47 (br. s., 3H), 2.56 (s, 3H) 398

318 557.2, 559.2 1.21 45- 100% 20 min, 100% 5 min ¹H NMR (500 MHz,CDCl₃) δ 8.67 (s, 1H), 8.47 (s, 1H), 7.70 (s, 1H), 7.33 (d, J = 6.9 Hz,1H), 7.20 (br. s., 1H), 6.10 (s, 1H), 5.19 (br. s., 1H), 4.46 (br. s.,2H), 4.32 (d, J = 5.5 Hz, 2H), 4.27 (br. s., 2H), 4.06 (s, 3H), 3.78 (s,3H), 2.60 (s, 3H) 399

318 557.2, 559.2 1.18 45- 80% 20 min, 100% 7 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.61 (s, 1H), 8.47 (s, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.74(s, 1H), 7.58 (br. s., 1H), 7.47 (s, 1H), 7.24 (s, 1H), 4.31 (d, J = 8.2Hz, 4H), 4.01 (s, 3H), 3.97 (d, J = 5.8 Hz, 2H), 3.71 (s, 3H), 2.57 (s,3H) 400

I-69 580.2, 582.2 1.30 50- 100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.04 (s, 2H), 8.73 (s, 1H), 8.58 (s, 1H), 8.03 (d, J = 7.6Hz, 1H), 7.86 (s, 1H), 5.36 (br. s., 1H), 4.53-4.45 (m, 1H), 4.38 (dd, J= 10.8, 6.0 Hz, 1H), 4.13 (s, 3H), 2.69 (s, 3H), 1.51 (d, J = 6.4 Hz,3H) 401

I-69 590.2, 592.2 1.34 50- 100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.80 (s, 2H), 8.74 (s, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.04(d, J = 7.7 Hz, 1H), 7.86 (s, 1H), 5.27 (td, J = 6.3, 3.0 Hz, 1H),4.44-4.39 (m, 1H), 4.32 (dd, J = 10.9, 5.9 Hz, 1H), 4.09 (s, 3H), 2.65(s, 3H), 1.43 (d, J = 6.6 Hz, 3H) 402

I-69 586.1, 588.1 1.35 50- 100% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 8.69 (s, 1H), 8.54 (s, 1H), 8.13 (br. s., 1H), 7.98 (d, J =7.3 Hz, 1H), 7.91 (br. s., 1H), 7.81 (s, 1H), 5.31 (br. s., 1H),4.47-4.39 (m, 1H), 4.34 (dd, J = 10.4, 6.1 Hz, 1H), 4.12 (s, 3H), 2.67(s, 3H), 2.25 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H) 403

I-69 632.0, 634.0, 636.0 1.30 60- 90% 20 min, 100% 5 min ¹H NMR (400MHz, THF) δ 9.25 (br. s., 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.60 (s, 1H),8.41 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 8.7, 2.8 Hz, 1H), 7.83 (dd, J =1.8, 0.9 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H),5.42-5.26 (m, 1H), 4.44-4.27 (m, 2H), 4.15 (s, 3H), 2.70 (s, 3H),1.55-1.49 (m, 3H) 404

I-81 568.2, 570.2 1.10 40- 80% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 10.07 (br. s., 1H), 8.67 (br. s., 1H), 8.62 (s, 1H), 8.48 (s,1H), 8.24 (br. s., 1H), 7.98 (d, J = 6.7 Hz, 2H), 7.75 (s, 1H), 7.45(br. s., 1H), 5.08 (d, J = 6.7 Hz, 1H), 4.76 (br. s., 1H), 4.01 (s, 3H),2.57 (s, 3H), 1.36 (d, J = 6.1 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H) 405

I-72 548.1 1.05 15- 100% 15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ9.81 (br. s., 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.49 (br. s., 1H), 8.02(d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 7.77 (br.s., 1H), 7.19 (d, J = 7.9 Hz, 1H), 5.09 (d, J = 4.6 Hz, 1H), 4.77 (br.s., 1H), 4.07 (s, 3H), 2.61 (s, 3H), 2.37 (s, 3H), 1.38 (m, 6H) 406

I-72 590.1 1.22 25- 100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ11.47 (s, 1H), 9.67 (br. s., 1H), 8.69 (s, 1H), 8.54 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.94 (d, J = 11.3 Hz, 1H), 7.81 (s, 1H), 7.45 (br. s.,1H), 7.12 (br. s., 1H), 6.96 (d, J = 8.2 Hz, 1H), 5.07 (d, J = 6.4 Hz,1H), 4.77 (br. s., 1H), 4.06 (s, 3H), 2.61 (s, 3H), 1.38 (d, J = 6.4 Hz,3H), 1.36 (d, J = 6.7 Hz, 3H) 407

I-72 565.1 1.26 50- 100% 15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ9.88 (br. s., 1H), 8.77 (s, 1H), 8.68 (br. s., 2H), 8.62 (s, 1H), 8.09(d, J = 7.9 Hz, 1H), 8.01 (d, J = 11.6 Hz, 1H), 7.88 (s, 1H), 5.15 (d, J= 6.4 Hz, 1H), 4.87 (d, J = 6.4 Hz, 1H), 4.14 (s, 3H), 3.90 (s, 3H),2.68 (s, 3H), 1.48- 1.40 (m, 6H) 408

I-67 551.1 1.22 50- 100% 12 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ9.91 (br. s., 1H), 8.69 (s, 1H), 8.63 (br. s., 2H), 8.52 (s, 1H), 7.99-7.90 (m, 2H), 7.78 (s, 1H), 5.23 (br. s., 1H), 4.38- 4.31 (m, 1H),4.29-4.21 (m, 1H), 4.06 (s, 3H), 3.85 (s, 3H), 2.60 (s, 3H), 1.40 (d, J= 6.4 Hz, 3H) 409

I-67 521.1 1.22 45- 78% 25 min, 100% 7 min ¹H NMR (400 MHz, DMSO-d₆) δ10.20 (br. s., 1H), 8.89 (s, 2H), 8.84 (s, 1H), 8.73 (s, 1H), 8.56 (d, J= 2.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 11.7 Hz, 1H), 7.82(dd, J = 2.0, 0.9 Hz, 1H), 5.35-5.22 (m, 1H), 4.43-4.35 (m, 1H),4.33-4.25 (m, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H)410

I-72 535.1 1.25 45- 90% 20 min, 100% 5 min ¹H NMR (400 MHz, DMSO-d₆) δ10.13 (br. s., 1H), 8.87 (s, 2H), 8.82 (s, 1H), 8.73 (s, 1H), 8.58 (d, J= 1.8 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 11.7 Hz, 1H), 7.84(dd, J = 2.0, 0.9 Hz, 1H), 5.14 (qd, J = 6.4, 2.8 Hz, 1H), 4.87-4.77 (m,1H), 4.09 (s, 3H), 2.64 (s, 3H), 1.44-1.38 (m, 6H) 411

I-67 519.2 1.27 45- 90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ9.73 (br. s., 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7.99-7.91 (m, 2H), 7.80(s, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.00 (t, J= 7.3 Hz, 1H), 5.25 (br. s., 1H), 4.38- 4.31 (m, 1H), 4.30-4.22 (m, 1H),4.07 (s, 3H), 2.61 (s, 3H), 1.42 (d, J = 6.1 Hz, 3H) 412

I-72 564.1 1.12 70- 100% 20 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ10.09 (s, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H),7.97-7.91 (m, 2H), 7.78 (s, 1H), 7.01 (d, J = 5.4 Hz, 1H), 6.91 (s, 1H),5.12 (dd, J = 6.4, 2.4 Hz, 1H), 4.79 (d, J = 3.7 Hz, 1H), 4.06 (s, 3H),3.77 (s, 3H), 2.60 (s, 3H), 1.39 (m, 6H) 413

I-72 535.1 1.06 40- 95% 21 min, 100% 6 min ¹H NMR (500 MHz, DMSO-d₆) δ10.54 (br. s., 1H), 9.19 (br. s., 1H), 9.00 (br. s., 1H), 8.68 (s, 1H),8.53 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.81(br. s., 2H), 5.16 (br. s., 1H), 4.81 (br. s., 1H), 4.07 (s, 3H), 2.62(s, 3H), 1.41 (d, J = 5.8 Hz, 6H) 414

I-72 577.2 1.27 45- 100% 10 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ9.90 (br. s., 1H), 8.72 (br. s., 2H), 8.66 (s, 1H), 8.51 (s, 1H), 7.99(d, J = 8.2 Hz, 1H), 7.91 (d, J = 11.3 Hz, 1H), 7.78 (s, 1H), 5.09 (d, J= 4.3 Hz, 1H), 4.80 (d, J = 3.7 Hz, 1H), 4.05 (s, 3H), 2.71 (t, J = 7.3Hz, 2H), 2.59 (s, 3H), 1.66 (sxt, J = 7.3 Hz, 2H), 1.38 (t, J = 5.8 Hz,6H), 0.83 (t, J = 7.3 Hz, 3H) 415

I-72 603.1 1.31 60- 100% 22 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.51 (br. s., 1H), 9.01 (s, 2H), 8.64 (s, 1H), 8.49 (s, 1H), 7.99 (d, J= 8.1 Hz, 1H), 7.91 (d, J = 11.4 Hz, 1H), 7.77 (s, 1H), 5.14 (dd, J =6.6, 2.2 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 4.05 (s, 3H), 2.59 (s, 3H),1.40 (d, J = 5.7 Hz, 6H) 416

I-72 549.2 1.11 55- 95% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.64 (s, 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H),7.94 (d, J = 10.4 Hz, 2H), 7.83 (s, 1H), 7.52 (d, J = 9.2 Hz, 1H), 5.13(d, J = 6.7 Hz, 1H), 4.76 (d, J = 5.8 Hz, 1H), 4.08 (s, 3H), 2.63 (s,3H), 2.50 (s, 3H-buried under d-DMSO), 1.41 (d, J = 6.4 Hz, 3H), 1.38(d, J = 6.4 Hz, 3H) 417

I-72 549.2 1.27 60- 100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.38 (s, 1H), 8.96 (s, 1H), 8.72 (br. s., 1H), 8.57 (br. s., 1H), 8.25(s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 11.3 Hz, 1H), 7.84 (br.s., 1H), 5.19 (dd, J = 6.4, 2.7 Hz, 1H), 4.82 (d, J = 3.4 Hz, 1H), 4.12(s, 3H), 2.66 (s, 3H), 2.46 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H), 1.44 (d,J = 6.7 Hz, 3H) 418

I-72 549.1 1.15 50- 100% 19 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.35 (s, 1H), 9.04 (br. s., 1H), 8.72 (s, 1H), 8.56 (d, J = 1.5 Hz,1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.83 (s, 1H),7.60 (s, 1H), 5.20-5.09 (m, 1H), 4.82 (dd, J = 6.4, 2.7 Hz, 1H), 4.08(s, 3H), 2.63 (s, 3H), 2.51 (br. s., 3H-Buried under d-DMSO signal),1.41 (d, J = 6.4 Hz, 6H) 419

I-72 548.2 1.26 25- 100% 15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.19 (br. s., 1H), 8.73 (s, 1H), 8.61 (br. s., 1H), 8.57 (s, 1H), 8.23(s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.99-7.91 (m, 2H), 7.84 (s, 1H), 5.13(d, J = 6.4 Hz, 1H), 4.82 (d, J = 5.8 Hz, 1H), 4.09 (s, 3H), 2.63 (s,3H), 2.32 (s, 3H), 1.41 (d, J = 4.6 Hz, 6H) 420

I-72 564.2 1.28 30- 100% 15 min, 100% 5 min (Meth C) ¹H NMR (500 MHz,DMSO-d₆) δ 10.06 (br. s., 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.31 (br. s.,1H), 8.08- 8.00 (m, 2H), 7.96 (d, J = 11.3 Hz, 1H), 7.83 (s, 1H), 7.64(br. s., 1H), 5.12 (d, J = 6.4 Hz, 1H), 4.81 (d, J = 6.1 Hz, 1H), 4.08(s, 3H), 3.81 (s, 2H), 2.63 (s, 3H), 1.40 (t, J = 5.3 Hz, 6H) 421

I-72 559.3 1.49 50- 100% 10 min, 100% 10 min (Meth C) ¹H NMR (500 MHz,DMSO-d₆) δ 10.27 (br. s., 1H), 8.83 (br. s., 1H), 8.71 (s, 1H), 8.61 (s,1H), 8.56 (s, 1H), 8.25 (br. s., 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.95 (d,J = 11.3 Hz, 1H), 7.82 (s, 1H), 5.13 (d, J = 6.4 Hz, 1H), 4.83 (d, J =6.1 Hz, 1H), 4.08 (s, 3H), 2.63 (s, 3H), 1.41 (d, J = 6.1 Hz, 6H) 422

I-72 578.2 1.45 60- 100% 10 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ9.50 (br. s., 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.02 (d, J = 7.9 Hz, 2H),7.95 (d, J = 11.3 Hz, 1H), 7.82 (s, 1H), 7.59 (br. s., 1H), 5.06 (d, J =5.2 Hz, 1H), 4.79 (d, J = 5.8 Hz, 1H), 4.08 (s, 3H), 3.80 (s, 3H), 2.63(s, 3H), 2.08 (s, 3H), 1.38 (t, J = 7.6 Hz, 6H) 423

I-72 534.0 1.00 60- 100% 20 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ9.93 (br. s., 1H), 8.72 (s, 1H), 8.66 (br. s., 1H), 8.56 (s, 1H), 8.22(d, J = 4.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz,1H), 7.91 (br. s., 1H), 7.83 (s, 1H), 7.35 (dd, J = 8.1, 4.7 Hz, 1H),5.13 (d, J = 6.4 Hz, 1H), 4.80 (d, J = 3.7 Hz, 1H), 4.09 (s, 3H), 2.63(s, 3H), 1.41 (t, J = 6.3 Hz, 6H) 424

I-66 520.9 1.10 45- 90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.16 (br. s., 1H), 8.77 (d, J = 4.3 Hz, 3H), 8.59 (s, 1H), 8.06-7.97(m, 2H), 7.86 (s, 1H), 4.57 (br. s., 2H), 4.46 (br. s., 2H), 4.10 (s,3H), 2.65 (s, 3H), 2.56 (s, 3H) 425

I-81 582.9, 584.9 1.26 60- 100% 20 min, 100% 7 min (Meth C) ¹H NMR (500MHz, DMSO-d₆) δ 9.95 (br. s., 1H), 8.78-8.67 (m, 3H), 8.57 (s, 1H), 8.06(d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 5.13 (dd, J = 6.6, 2.3 Hz, 1H), 4.85(d, J = 6.4 Hz, 1H), 4.09 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H), 1.42 (d,J = 6.4 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H)

Example 426(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(6-(morpholine-4-carbonyl)pyridin-3-yl)carbamate

To a vial charged with Intermediate I-74 (10 mg, 0.017 mmol) was addedDCM (1 mL). To this solution was added magnesium chloride (16.09 mg,0.169 mmol) followed by morpholine (0.1 mL, 1.148 mmol). The resultingmixture was sealed, stirred vigorously and heated to 65° C. overnightbefore being diluted with EtOAc, filtered over Celite, concentrated, andpurified by Prep HPLC (Method C, 25-100% over 15 min, hold 100% for 5min) to afford Example 426 (9.6 mg, 0.015 mmol, 86% yield). LC-MS:Method H, RT=1.20 min, MS (ESI) m/z: 647.2 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 10.12 (br. s., 1H), 8.64 (s, 1H), 8.59 (br. s., 1H), 8.49 (s,1H), 7.98 (d, J=7.9 Hz, 2H), 7.91 (d, J=11.6 Hz, 1H), 7.76 (s, 1H), 7.57(d, J=8.5 Hz, 1H), 5.12 (d, J=4.6 Hz, 1H), 4.80 (d, J=5.8 Hz, 1H), 4.05(s, 3H), 3.62 (d, J=15.9 Hz, 2H), 3.49 (d, J=17.1 Hz, 2H), 2.59 (s, 3H),2.52 (br. s., 4H), 1.39 (m, 6H).

Preparation of Amide Examples

The amides in the accompanying table were prepared according to thefollowing three general procedures, which are analogous to the ones usedto synthesize Examples 391-392 and 426 described above.

Primary Amides

To a vial charged with the appropriately substituted hetero-aryl ester(1.0 equiv) was added ammonia (7M solution in MeOH) (0.02 M). Theresulting mixture was sealed and heated to 65° C. overnight before beingconcentrated and purified by Prep HPLC (Method D unless otherwiseindicated) to afford the desired example.

Secondary Amides

To a solution of the appropriately substituted hetero-aryl ester (1.0equiv) in THF (0.02 M) was added the desired amine (100 equiv). Theresulting mixture was sealed and heated to 65° C. overnight before beingconcentrated and purified by Prep HPLC (Method D unless otherwiseindicated) to afford the desired example.

Tertiary Amides

To a solution of the appropriately substituted hetero-aryl ester (1.0equiv) in DCM (0.02 M) was added MgCl₂ (10 equiv) followed by thedesired amine (100 equiv). The resulting mixture was sealed, stirredvigorously and heated to 65° C. overnight before being diluted withEtOAc, filtered over Celite, concentrated and purified by Prep HPLC(Method D unless otherwise indicated) to afford the desired example.

LCMS LCMS RT HPLC [M + (Min) Prep Ex. H]⁺ Method Method No. StructureEster m/z H D NMR 427

I-87 597.1, 599.2 1.16 45-95% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 10.44 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.42 (d, J = 5.2Hz, 1H), 8.15 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.83 (s, 1H), 7.63 (br.s., 1H), 7.57 (br. s., 1H), 5.30 (br. s., 1H), 4.46-4.37 (m, 1H), 4.31(d, J = 5.8 Hz, 1H), 4.07 (s, 3H), 2.64 (s, 3H), 1.44 (d, J = 6.1 Hz,3H) 428

I-87 611.1, 613.1 1.17 45-95% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 10.42 (s, 1H), 8.71-8.63 (m, 2H), 8.54 (s, 1H), 8.42 (d, J =5.5 Hz, 1H), 8.13 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.62(d, J = 4.9 Hz, 1H), 5.29 (br. s., 1H), 4.40 (d, J = 8.5 Hz, 1H), 4.30(dd, J = 10.5, 6.3 Hz, 1H), 4.07 (s, 3H), 2.78 (d, J = 4.9 Hz, 3H), 2.63(s, 3H), 1.43 (d, J = 6.4 Hz, 3H) 429

I-84 564.1 1.10 60-100% 13 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ8.94 (s, 2H), 8.65 (s, 1H), 8.48 (s, 1H), 8.05 (br. s., 1H), 7.94 (d, J= 8.2 Hz, 1H), 7.91 (d, J = 11.6 Hz, 1H), 7.75 (s, 1H), 7.63 (br. s.,1H), 5.32-5.17 (m, 1H), 4.39-4.30 (m, 1H), 4.29-4.21 (m, 1H), 4.02 (s,3H), 2.56 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H) 430

I-84 578.1 1.12 50-100% 10 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ8.97 (s, 2H), 8.77-8.69 (m, 2H), 8.55 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H),7.97 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 5.29 (br. s., 1H), 4.40 (d, J =8.2 Hz, 1H), 4.29 (dd, J = 10.7, 6.1 Hz, 1H), 4.07 (s, 3H), 2.78 (d, J =4.6 Hz, 3H), 2.62 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H) 431

I-84 592.2 1.15 60-100% 13 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.39 (br. s., 1H), 8.92 (s, 2H), 8.71 (s, 1H), 8.54 (s, 1H), 7.99 (d, J= 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 5.29 (d, J = 2.7Hz, 1H), 4.42-4.35 (m, 1H), 4.32-4.25 (m, 1H), 4.06 (s, 3H), 2.98 (s,3H), 2.77 (s, 3H), 2.61 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H) 432

I-82 577.2 1.17 15-100% 20 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ10.26 (br. s., 1H), 8.68 (s, 2H), 8.59 (d, J = 4.6 Hz, 1H), 8.52 (s,1H), 8.02 (d, J = 8.9 Hz, 1H), 7.99-7.90 (m, 3H), 7.79 (s, 1H), 5.27 (d,J = 3.1 Hz, 1H), 4.37 (d, J = 7.9 Hz, 1H), 4.31-4.23 (m, 1H), 4.06 (s,3H), 2.77 (d, J = 4.6 Hz, 3H), 2.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H)433

I-82 563.1 1.15 25-65% 20 min, 100% 9 min ¹H NMR (500 MHz, DMSO-d₆) δ10.24 (br. s., 1H), 8.64 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.03-7.97(m, 1H), 7.95-7.85 (m, 4H), 7.72 (s, 1H), 7.43 (br. s., 1H), 5.27-5.19(m, 1H), 4.36-4.29 (m, 1H), 4.26-4.19 (m, 1H), 4.01 (s, 3H), 2.55 (s,3H), 1.39 (d, J = 6.4 Hz, 3H) 434

I-82 591.1 1.16 10-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.19 (br. s., 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.02-7.89(m, 3H), 7.77 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 5.27 (d, J = 3.1 Hz,1H), 4.36 (d, J = 7.9 Hz, 1H), 4.31-4.23 (m, 1H), 4.05 (s, 3H), 2.97 (s,3H), 2.96 (s, 3H), 2.59 (s, 3H), 1.42 (d, J = 6.7 Hz, 3H) 435

I-82 633.1 1.17 10-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.22 (br. s., 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.98-7.90 (m, 2H), 7.77 (s, 1H), 7.59 (d, J = 8.5 Hz,1H), 5.27 (d, J = 2.7 Hz, 1H), 4.36 (d, J = 7.9 Hz, 1H), 4.27 (dd, J =10.7, 6.1 Hz, 1H), 4.05 (s, 3H), 3.62 (m, 4H), 3.52 (m, 4H), 2.59 (s,3H), 1.42 (d, J = 6.4 Hz, 3H) 436

I-74 591.1 1.18 25-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.13 (br. s., 1H), 8.67 (s, 1H), 8.64 (br. s., 1H), 8.55 (d, J = 4.6Hz, 1H), 8.52 (s, 1H), 8.04-7.96 (m, 2H), 7.95-7.88 (m, 2H), 7.79 (s,1H), 5.11 (dd, J = 6.4, 2.4 Hz, 1H), 4.82 (d, J = 4.0 Hz, 1H), 4.06 (s,3H), 2.76 (d, J = 4.6 Hz, 3H), 2.60 (s, 3H), 1.39 (m, 6H) 437

I-86 648.2 1.18 20-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.25 (br. s., 1H), 8.85 (s, 2H), 8.63 (s, 1H), 8.47 (s, 1H), 7.97 (d, J= 7.9 Hz, 1H), 7.88 (d, J = 11.6 Hz, 1H), 7.74 (s, 1H), 5.08 (dd, J =6.6, 2.6 Hz, 1H), 4.75 (m, 1H), 4.00 (s, 3H), 3.57 (m, 4H), 3.40 (br.s., 2H), 3.17-3.08 (br. s., 2H), 2.55 (s, 3H), 1.34 (m, 6H) 438

I-74 605.2 1.19 40-80% 20 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ10.07 (br. s., 1H), 8.65 (s, 1H), 8.58 (br. s., 1H), 8.50 (s, 1H), 7.98(d, J = 8.2 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 11.6 Hz,1H), 7.77 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 5.11 (d, J = 4.3 Hz, 1H),4.79 (d, J = 4.6 Hz, 1H), 4.04 (s, 3H), 2.95 (s, 3H), 2.91 (s, 3H), 2.58(s, 3H), 1.38 (m, 6H) 439

I-74 635.2 1.18 25-100% 15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.19 (br. s., 1H), 8.71-8.64 (m, 2H), 8.53 (s, 1H), 8.41 (t, J = 6.0Hz, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 11.0 Hz, 2H), 7.80 (s,1H), 5.12 (dd, J = 6.6, 2.3 Hz, 1H), 4.87-4.77 (m, 2H), 4.06 (s, 3H),3.75 (dt, J = 11.7, 5.6 Hz, 1H), 3.34 (br. s., 1H), 3.19-3.09 (m, 1H),2.61 (s, 3H), 1.40 (m, 6H), 1.04 (d, J = 6.4 Hz, 3H) 440

I-86 592.1 1.15 30-80% 18 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ8.93 (s, 2H), 8.71 (d, J = 4.9 Hz, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.02(d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.3 Hz, 1H), 7.79 (s, 1H), 5.13 (d, J= 4.3 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 4.06 (s, 3H), 2.76 (d, J = 4.9Hz, 3H), 2.60 (s, 3H), 1.40 (d, J = 6.4 Hz, 6H) 441

I-74 635.2 1.19 45-90% 22 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.18 (br. s., 1H), 8.66 (s, 2H), 8.52 (s, 1H), 8.41 (t, J = 5.8 Hz,1H), 8.00 (m, 2H), 7.94 (s, 1H), 7.92 (d, J = 4.6 Hz, 1H), 7.78 (s, 1H),5.12 (d, J = 6.4 Hz, 1H), 4.86 (d, J = 4.6 Hz, 1H), 4.81 (d, J = 6.1 Hz,1H), 4.05 (s, 3H), 3.75 (dt, J = 11.3, 5.6 Hz, 1H), 3.29 (dt, J = 12.4,6.1 Hz, 1H), 3.16-3.07 (m, 1H), 2.59 (s, 3H), 1.39 (t, J = 5.3 Hz, 6H),1.04 (d, J = 6.1 Hz, 3H) 442

I-83 607.1 1.08 45-90% 20 min, 100% 8 min ¹H NMR (500 MHz, DMSO-d₆) δ8.77 (s, 1H), 8.69 (t, J = 5.8 Hz, 1H), 8.60 (s, 1H), 8.50 (d, J = 5.5Hz, 1H), 8.22 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 11.6 Hz,1H), 7.86 (s, 1H), 7.72 (dd, J = 5.5, 1.8 Hz, 1H), 5.36 (d, J = 3.1 Hz,1H), 4.44 (d, J = 7.9 Hz, 1H), 4.38-4.31 (m, 1H), 4.13 (s, 3H), 3.57 (q,J = 5.6 Hz, 2H), 2.67 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H) 443

I-83 577.1 1.12 50-100% 20 min, 100% 8 min ¹H NMR (500 MHz, DMSO-d₆) δ10.52 (s, 1H), 8.77 (d, J = 4.9 Hz, 1H), 8.74 (s, 1H), 8.58 (s, 1H),8.49 (d, J = 5.5 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 8.00(d, J = 11.6 Hz, 1H), 7.84 (s, 1H), 7.70 (dd, J = 5.3, 2.0 Hz, 1H), 5.36(d, J = 2.7 Hz, 1H), 4.48-4.41 (m, 1H), 4.38-4.31 (m, 1H), 4.12 (s, 3H),2.86 (d, J = 4.9 Hz, 3H), 2.66 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H) 444

I-83 563.1 1.11 25-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.47 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H),8.15 (s, 1H), 8.05 (br. s., 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.94 (d, J =11.6 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J = 5.5 Hz, 1H), 7.60 (br. s., 1H),5.29 (br. s., 1H), 4.40-4.34 (m, 1H), 4.31-4.24 (m, 1H), 4.06 (s, 3H),2.60 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H) 445

I-82 607.0 1.22 30-70% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.29 (br. s., 1H), 8.70 (br. s., 1H), 8.65 (s, 1H), 8.57- 8.51 (m, 1H),8.50 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.00-7.89 (m, 3H), 7.77 (s, 1H),5.29 (br. s., 1H), 4.89 (t, J = 4.9 Hz, 1H), 4.42-4.34 (m, 1H),4.32-4.24 (m, 1H), 4.06 (s, 3H), 3.53-3.48 (m, 2H), 3.36 (d, J = 5.8 Hz,2H), 2.60 (s, 3H), 1.44 (d, J = 6.1 Hz, 3H) 446

I-74 663.1 1.28 50-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.15 (br. s., 1H), 8.70-8.59 (m, 3H), 8.50 (s, 1H), 8.04-7.97 (m, J =8.2 Hz, 2H), 7.94-7.88 (m, 2H), 7.77 (s, 1H), 5.13 (d, J = 6.1 Hz, 1H),4.83 (d, J = 5.8 Hz, 1H), 4.06 (s, 3H), 3.35 (m, 2H), 2.60 (s, 3H), 1.61(t, J = 7.2 Hz, 2H), 1.41 (t, J = 6.3 Hz, 6H), 1.14 (s, 6H) 447

I-83 591.0 1.14 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.41 (s, 1H), 8.65 (s, 1H), 8.49 (s, 1H), 8.38 (d, J = 5.5 Hz, 1H),7.96-7.89 (m, 2H), 7.76 (s, 1H), 7.59 (s, 1H), 7.51 (d, J = 5.5 Hz, 1H),5.29 (br. s., 1H), 4.37 (d, J = 9.8 Hz, 1H), 4.27 (dd, J = 10.5, 6.0 Hz,1H), 4.06 (s, 3H), 2.98 (s, 3H), 2.89 (s, 3H), 2.59 (s, 3H), 1.44 (d, J= 6.4 Hz, 3H) 448

I-82 635.1 1.24 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.30 (br. s., 1H), 8.70 (br. s., 1H), 8.64 (s, 1H), 8.48 (s, 1H),8.37-8.29 (m, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H),7.95-7.89 (m, 2H), 7.75 (s, 1H), 5.29 (br. s., 1H), 4.80 (s, 1H),4.41-4.34 (m, 1H), 4.31-4.24 (m, 1H), 4.05 (s, 3H), 3.26 (d, J = 5.8 Hz,2H), 2.59 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.10 (s, 6H) 449

I-82 621.2 1.18 45-90% 25 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.22 (br. s., 1H), 8.70-8.61 (m, 2H), 8.50 (s, 1H), 8.49-8.45 (m, 1H),8.01 (br. s., 1H), 7.96- 7.89 (m, 3H), 7.80 (s, 1H), 5.34-5.22 (m, J =8.1 Hz, 1H), 4.37 (d, J = 8.8 Hz, 1H), 4.30-4.22 (m, 1H), 4.05 (s, 3H),3.80 (m, 1H), 3.28 (d, J = 5.4 Hz, 1H), 3.20- 3.07 (m, 1H), 2.60 (s,3H), 1.40 (d, J = 6.4 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H) 450

I-82 621.2 1.18 45-90% 25 min, 100% 8 min ¹H NMR (500 MHz, DMSO-d₆) δ8.76 (s, 1H), 8.73 (s, 1H), 8.60 (s, 1H), 8.44 (br. s., 1H), 8.11-7.96(m, 4H), 7.86 (s, 1H), 5.31 (br. s., 1H), 4.84 (d, J = 4.9 Hz, 1H), 4.41(d, J = 8.5 Hz, 1H), 4.34-4.28 (m, 1H), 4.10 (s, 3H), 3.79 (br. s., 1H),3.39-3.28 (m, 1H), 3.21-3.12 (m, 1H), 2.65 (s, 3H), 1.45 (d, J = 6.4 Hz,3H), 1.07 (d, J = 6.1 Hz, 3H) 451

I-85 621.3 1.08 60-95% 20 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ10.39 (s, 1H), 8.68 (s, 1H), 8.62 (t, J = 5.7 Hz, 1H), 8.53 (s, 1H),8.42 (d, J = 5.7 Hz, 1H), 8.15 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.94(d, J = 11.8 Hz, 1H), 7.79 (s, 1H), 7.63 (d, J = 3.7 Hz, 1H), 5.15 (dd,J = 6.4, 2.4 Hz, 1H), 4.86-4.78 (m, 2H), 4.07 (s, 3H), 3.51 (q, J = 5.8Hz, 2H), 3.40-3.31 (m, 2H), 2.61 (s, 3H), 1.41 (d, J = 4.7 Hz, 6H) 452

I-85 653.3 1.11 60-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.39 (s, 1H), 8.69 (s, 1H), 8.60-8.51 (m, 2H), 8.43 (d, J = 5.7 Hz,1H), 8.16 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 11.4 Hz, 1H),7.80 (s, 1H), 7.63 (d, J = 4.0 Hz, 1H), 5.15 (dd, J = 6.4, 2.4 Hz, 1H),4.81 (dd, J = 6.4, 2.4 Hz, 1H), 4.07 (s, 3H), 3.82-3.71 (m, 1H),3.43-3.27 (m, 1H), 3.22-3.10 (m, 1H), 2.61 (s, 3H), 1.41 (m, 6H), 1.06(d, J = 6.1 Hz, 3H) 453

I-85 577.2 1.10 60-100% 18 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ10.38 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H), 8.42 (d, J = 5.7 Hz, 1H),8.16 (s, 1H), 8.08-8.01 (m, 2H), 7.95 (d, J = 11.4 Hz, 1H), 7.80 (s,1H), 7.66-7.56 (m, 2H), 5.15 (d, J = 4.4 Hz, 1H), 4.81 (d, J = 4.0 Hz,1H), 4.07 (s, 3H), 2.62 (s, 3H), 1.41 (m, 6H) 454

I-86 578.2 1.12 45-90% 20 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ10.39 (br. s., 1H), 8.97 (s, 2H), 8.71 (s, 1H), 8.55 (s, 1H), 8.09 (br.s., 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 11.4 Hz, 1H), 7.81 (s,1H), 7.67 (br. s., 1H), 5.21-5.11 (m, 1H), 4.83 (d, J = 4.0 Hz, 1H),4.08 (s, 3H), 2.62 (s, 3H), 1.42 (m, 6H) 455

I-86 622.3 1.09 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.38 (br. s., 1H), 8.96 (s, 2H), 8.70 (s, 1H), 8.64 (t, J = 5.9 Hz,1H), 8.55 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.4 Hz, 1H),7.81 (s, 1H), 5.15 (d, J = 6.7 Hz, 1H), 4.88-4.83 (m, 1H), 4.81 (t, J =5.6 Hz, 1H), 4.07 (s, 3H), 3.51 (q, J = 6.1 Hz, 2H), 3.34 (m, 2H), 2.62(s, 3H), 1.42 (m, 6H) 456

I-86 636.3 1.11 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.39 (br. s., 1H), 8.97 (br. s., 2H), 8.69 (s, 1H), 8.59- 8.50 (m, 2H),8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.1 Hz, 1H), 7.80 (s, 1H), 5.15(d, J = 6.4 Hz, 1H), 4.85 (d, J = 4.7 Hz, 2H), 4.07 (s, 3H), 3.83-3.71(m, 1H), 3.28 (dt, J = 12.4, 6.1 Hz, 1H), 3.16 (dt, J = 12.9, 6.2 Hz,1H), 2.62 (s, 3H), 1.42 (m, 6H), 1.06 (d, J = 6.1 Hz, 3H) 457

I-86 650.3 1.13 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.40 (br. s., 1H), 8.98 (s, 2H), 8.69 (s, 1H), 8.54 (s, 1H), 8.39 (t, J= 6.1 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.1 Hz, 1H), 7.81(s, 1H), 5.15 (d, J = 4.4 Hz, 1H), 4.85 (d, J = 4.0 Hz, 1H), 4.71 (s,1H), 4.07 (s, 3H), 3.25 (d, J = 6.4 Hz, 2H), 2.62 (s, 3H), 1.42 (m, 6H),1.10 (s, 6H) 458

I-86 664.2 1.14 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.35 (br. s., 1H), 8.94 (s, 2H), 8.79 (t, J = 5.6 Hz, 1H), 8.68 (s,1H), 8.53 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 11.8 Hz, 1H),7.79 (s, 1H), 5.20-5.09 (m, 1H), 4.85 (d, J = 4.0 Hz, 1H), 4.47 (s, 1H),4.07 (s, 3H), 3.38- 3.30 (m, 2H), 2.61 (s, 3H), 1.62 (t, J = 7.4 Hz,2H), 1.41 (m, 6H), 1.14 (s, 6H) 459

I-85 664.2 1.14 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.35 (br. s., 1H), 8.94 (s, 2H), 8.79 (t, J = 5.6 Hz, 1H), 8.68 (s,1H), 8.53 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 11.8 Hz, 1H),7.79 (s, 1H), 5.20-5.09 (m, 1H), 4.85 (d, J = 4.0 Hz, 1H), 4.47 (s, 1H),4.07 (s, 3H), 3.38-3.30 (m, 2H), 2.61 (s, 3H), 1.62 (t, J = 7.4 Hz, 2H),1.41 (m, 6H), 1.14 (s, 6H) 460

I-74 649.3 1.19 55-95% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.21 (br. s., 1H), 8.68 (s, 2H), 8.53 (s, 1H), 8.30 (t, J = 6.1 Hz,1H), 8.09-8.00 (m, 2H), 7.99-7.90 (m, 2H), 7.80 (s, 1H), 5.14 (dd, J =6.4, 2.4 Hz, 1H), 4.83 (d, J = 3.7 Hz, 1H), 4.07 (s, 3H), 3.24 (d, J =6.4 Hz, 2H), 2.61 (s, 3H), 1.45-1.37 (m, 6H), 1.09 (s, 6H) 461

I-85 635.2 1.11 60-100% 18 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.39 (s, 1H), 8.68 (s, 1H), 8.60-8.50 (m, 2H), 8.42 (d, J = 5.7 Hz,1H), 8.15 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 11.8 Hz, 1H),7.79 (s, 1H), 7.63 (d, J = 3.7 Hz, 1H), 5.15 (dd, J = 6.6, 2.5 Hz, 1H),4.88 (d, J = 4.7 Hz, 1H), 4.81 (dd, J = 6.2, 2.5 Hz, 1H), 4.06 (s, 3H),3.77 (dt, J = 11.4, 5.6 Hz, 1H), 3.36- 3.27 (m, 1H), 3.20-3.10 (m, 1H),2.61 (s, 3H), 1.47-1.35 (m, 6H), 1.05 (d, J = 6.1 Hz, 3H) 462

I-86 636.3 1.11 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.38 (br. s., 1H), 8.96 (br. s., 2H), 8.67 (s, 1H), 8.56 (t, J = 5.7Hz, 1H), 8.52 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 11.4 Hz,1H), 7.79 (s, 1H), 5.15 (dd, J = 6.6, 2.2 Hz, 1H), 4.90-4.79 (m, 2H),4.07 (s, 3H), 3.78 (dt, J = 11.3, 5.8 Hz, 1H), 3.29 (dt, J = 12.2, 6.2Hz, 1H), 3.20-3.10 (m, 1H), 2.61 (s, 3H), 1.41 (m, 6H), 1.06 (d, J = 6.1Hz, 3H) 463

I-86 662.3 1.15 50-100% 22 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ10.41 (br. s., 1H), 8.97 (s, 2H), 8.70 (s, 1H), 8.55 (s, 1H), 8.36 (t, J= 5.9 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 11.8 Hz, 1H), 7.81(s, 1H), 5.40 (s, 1H), 5.20-5.09 (m, 1H), 4.85 (d, J = 6.1 Hz, 1H), 4.08(s, 3H), 2.62 (s, 3H), 2.01-1.87 (m, 4H), 1.70-1.57 (m, 1H), 1.56-1.43(m, 1H), 1.42 (m, 6H) 464

I-82 649.2 1.21 45-90% 19 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ8.81 (s, 1H), 8.75 (br. s., 2H), 8.65 (br. s., 1H), 8.18- 7.99 (m, 4H),7.91 (br. s., 1H), 5.37 (br. s., 1H), 4.46 (br. s., 1H), 4.38 (br. s.,1H), 4.16 (s, 43), 3.46 (m, 2H), 2.71 (s, 3H), 1.70 (m, 2H), 1.51 (d, J= 6.4 Hz, 3H), 1.22 (s, 6H) 465

I-85 649.3 1.14 40-80% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.37 (s, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.44 (d, J = 5.2 Hz, 2H),8.17 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.81(s, 1H), 7.66-7.60 (m, 1H), 5.15 (dd, J = 6.7, 2.4 Hz, 1H), 4.81 (dd, J= 6.1, 2.4 Hz, 1H), 4.74 (s, 1H), 4.08 (s, 3H), 3.26 (d, J = 6.1 Hz,2H), 2.62 (s, 3H), 1.41 (m, 6H), 1.10 (s, 6H) 466

I-85 591.1 1.15 45-90% 25 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ10.34 (s, 1H), 8.73-8.62 (m, 2H), 8.54 (s, 1H), 8.41 (d, J = 4.9 Hz,1H), 8.13 (br. s., 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 11.6 Hz,1H), 7.80 (s, 1H), 7.62 (br. s., 1H), 5.15 (dd, J = 6.4, 2.7 Hz, 1H),4.81 (dd, J = 6.3, 2.6 Hz, 1H), 4.07 (s, 3H), 2.79 (d, J = 4.6 Hz, 3H),2.62 (s, 3H), 1.41 (m, 6H) 467

I-85 605.1 1.08 40-75% 25 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ10.30 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.36 (d, J = 5.5 Hz, 1H),8.02 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 7.58(s, 1H), 7.51-7.43 (m, 1H), 5.14 (dd, J = 6.6, 2.6 Hz, 1H), 4.81 (dd, J= 6.3, 2.6 Hz, 1H), 4.07 (s, 3H), 2.98 (s, 3H), 2.89 (s, 3H), 2.61 (s,3H), 1.41 (m, 6H) 468

I-86 606.2 1.19 45-90% 22 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ10.27 (br. s., 1H), 8.91 (s, 2H), 8.69 (s, 1H), 8.53 (s, 1H), 8.03 (d, J= 7.9 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 5.15 (dd, J =6.6, 2.6 Hz, 1H), 4.87-4.76 (m, 1H), 4.07 (s, 3H), 2.99 (s, 3H), 2.76(s, 3H), 2.62 (s, 3H), 1.45-1.37 (m, 6H) 469

I-82 607.9 1.06 45-80% 25 min, 80% 4 min ¹H NMR (500 MHz, DMSO-d₆) δ8.97 (s, 2H), 8.67 (t, J = 5.8 Hz, 1H), 8.64 (s, 1H), 8.48 (s, 1H),7.95-7.87 (m, 2H), 7.75 (s, 1H), 5.35-5.23 (m, 1H), 4.94-4.88 (m, 1H),4.38 (d, J = 8.2 Hz, 1H), 4.28 (dd, J = 10.7, 6.1 Hz, 1H), 4.05 (s, 3H),3.55-3.49 (m, 2H), 3.36 (q, J = 6.0 Hz, 2H), 2.59 (s, 3H), 1.44 (d, J =6.4 Hz, 3H)

Preparation of Hindered Amide Examples

The sterically hindered amides in the accompanying table were preparedaccording to the following two-step procedure.

Saponification

To a solution of the appropriately substituted hetero-aryl ester (1.0equiv) in THF (0.05 M) was added a 1 M solution of LiOH (5 equiv). Theresulting mixture was stirred vigorously at for 3 h before beingquenched with a 1 M solution of HCl (10 equiv). The solution wasconcentrated to a crude residue in vacuo and taken on to the subsequentHATU coupling without purification.

HATU Coupling

The crude saponified residue above (1.0 equiv) was retaken in DMF (0.1M) and stirred at room temperature. To this solution was addeddiisopropylethylamine (10 equiv) and the appropriate amine substrate(1.5 equiv) followed by HATU (1.5 equiv). The resulting mixture wasstirred for 10 min before being quenched with methanol (100 equiv),concentrated, and purified by Prep HPLC (Method D, unless otherwiseindicated) to afford the desired example.

LCMS RT HPLC LCMS (Min) Prep Ex. [M + H]⁺ Method Method No. StructureEster m/z H D NMR 470

I-82 663.1 1.13 45-90% 20 min, 100% 6 min ¹H NMR (500 MHz, DMSO-d₆) δ10.29 (br. s., 1H), 8.87 (t, J = 6.3 Hz, 1H), 8.72 (s, 1H), 8.69 (s,1H), 8.53 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.02-7.91 (m, 3H), 7.79 (s,1H), 5.30 (d, J = 3.1 Hz, 1H), 5.05 (t, J = 5.5 Hz, 1H), 4.39 (d, J =6.1 Hz, 3H), 4.33-4.23 (m, 3H), 4.07 (s, 3H), 3.64-3.54 (m, 4H), 2.61(s, 3H), 1.44 (d, J = 6.4 Hz, 3H) 471

I-82 621.2 1.10 30-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.22 (br. s., 1H), 8.73 (s, 1H), 8.71-8.64 (m, 1H), 8.57 (s, 1H), 8.06(d, J = 8.5 Hz, 1H), 8.03-7.96 (m, 2H), 7.85 (s, 1H), 7.59 (d, J = 8.5Hz, 1H), 5.35 (br. s., 1H), 4.43 (d, J = 8.5 Hz, 1H), 4.38-4.30 (m, 1H),4.13 (s, 3H), 3.56 (br. s., 3H), 3.47 (br. s., 1H), 3.06 (br. s., 3H),2.67 (s, 3H), 1.49 (d, J = 6.1 Hz, 3H) 472

I-82 649.2 1.22 35-100% 20 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ10.32 (br. s., 1H), 8.79 (s, 1H), 8.76 (br. s., 1H), 8.68 (br. s., 1H),8.63 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.08-8.01 (m, 3H), 7.90 (s, 1H),5.37 (br. s., 1H), 4.47 (d, J = 8.5 Hz, 1H), 4.38 (br. s., 1H), 4.16 (s,3H), 3.28- 3.21 (m, 5H), 2.70 (s, 3H), 1.51 (d, J = 6.1 Hz, 3H), 0.89(s, 6H) 473

I-82 661.3 1.19 50-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.25 (br. s., 1H), 8.72 (s, 1H), 8.66 (d, J = 12.2 Hz, 2H), 8.56 (s,1H), 8.06 (d, J = 10.4 Hz, 1H), 8.01-7.93 (m, 3H), 7.84 (s, 1H), 5.29(br. s., 1H), 4.43-4.37 (m, 1H), 4.33- 4.25 (m, 1H), 4.09 (s, 3H), 3.40(br. s., 4H), 2.63 (s, 3H), 1.86-1.65 (m, 6H), 1.43 (d, J = 6.4 Hz, 3H)474

I-82 649.2 1.15 45-100% 11 min, 100% 6 min ¹H NMR (500 MHz, DMSO-d₆) δ10.16 (d, J = 12.2 Hz, 1H), 8.65 (s, 1H), 8.64- 8.57 (m, 1H), 8.49 (s,1H), 7.99 (br. s., 1H), 7.95-7.88 (m, 2H), 7.77 (s, 1H), 7.56-7.46 (m,1H), 5.28 (br. s., 1H), 4.36 (d, J = 10.1 Hz, 1H), 4.31-4.24 (m, 1H),4.06 (s, 3H), 3.58 (s, 2H), 3.10-3.00 (m, 3H), 2.60 (s, 3H), 1.43 (d, J= 6.4 Hz, 3H), 1.15 (s, 3H), 0.91 (s, 3H) 475

I-82 633.2 1.10 45-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.19 (d, J = 6.1 Hz, 1H), 8.64 (s, 2H), 8.49 (s, 1H), 8.01 (d, J = 8.5Hz, 1H), 7.96-7.85 (m, 2H), 7.79-7.67 (m, 2H), 5.28 (br. s., 1H),4.41-4.33 (m, 1H), 4.33-4.23 (m, 2H), 4.06 (s, 3H), 3.81-3.59 (m, 2H),3.54-3.37 (m, 2H), 2.59 (s, 3H), 1.96- 1.85 (m, 1H), 1.80 (br. s., 1H),1.43 (d, J = 6.4 Hz, 3H) 476

I-82 647.2 1.10 35-75% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.18 (br. s., 1H), 8.68-8.59 (m, 2H), 8.50 (s, 1H), 8.00 (br. s., 1H),7.96-7.88 (m, 2H), 7.77 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 5.28 (br. s.,1H), 4.41-4.34 (m, 1H), 4.28 (dd, J = 10.7, 6.1 Hz, 1H), 4.06 (s, 3H),3.79-3.66 (m, 1H), 3.49-3.35 (m, 3H), 3.34-3.28 (m, 1H), 3.27-3.20 (m,1H), 2.60 (s, 3H), 2.34-2.24 (m, 1H), 1.96- 1.85 (m, 1H), 1.67-1.55 (m,1H), 1.43 (d, J = 6.4 Hz, 3H) 477

I-82 663.3 1.10 40-85% 16 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.20 (br. s., 1H), 8.67 (s, 1H), 8.63 (br. s., 1H), 8.51 (s, 1H), 8.02(d, J = 8.5 Hz, 1H), 7.97-7.89 (m, 2H), 7.78 (s, 1H), 7.59 (d, J = 8.5Hz, 1H), 5.28 (br. s., 1H), 4.46- 4.33 (m, 2H), 4.28 (dd, J = 10.5, 6.0Hz, 1H), 4.06 (s, 3H), 3.97-3.84 (m, 1H), 3.77 (br. s., 1H), 3.51-3.33(m, 3H), 3.31-3.11 (m, 1H), 3.02-2.88 (m, 1H), 2.67 (d, J = 10.1 Hz,1H), 2.60 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H) 478

I-82 633.2 1.10 35-95% 20 min 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.18 (br. s., 1H), 8.67-8.59 (m, 2H), 8.49 (s, 1H), 8.01 (br. s., 1H),7.95-7.87 (m, 2H), 7.76 (s, 1H), 7.72 (dd, J = 12.5, 8.5 Hz, 1H), 5.28(d, J = 3.1 Hz, 1H), 4.37 (d, J = 9.5 Hz, 1H), 4.27 (dd, J = 10.5, 6.0Hz, 2H), 4.05 (s, 3H), 3.78-3.69 (m, 1H), 3.59 (s, 2H), 3.52 (d, J =11.6 Hz, 1H), 3.42 (d, J = 13.1 Hz, 1H), 2.59 (s, 3H), 1.90 (dd, J =8.9, 4.0 Hz, 1H), 1.80 (br. s., 1H), 1.43 (d, J = 6.4 Hz, 3H) 479

I-82 647.2 1.10 45-90% 19 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.18 (br. s., 1H), 8.65 (s, 1H), 8.62 (br. s., 1H), 8.50 (s, 1H), 8.01(t, J = 7.3 Hz, 1H), 7.95- 7.88 (m, 2H), 7.77 (s, 1H), 7.73-7.68 (m,1H), 6.62 (d, J = 8.5 Hz, 1H), 5.28 (br. s., 1H), 4.37 (d, J = 8.2 Hz,1H), 4.28 (dd, J = 10.8, 6.3 Hz, 1H), 4.06 (s, 3H), 3.78- 3.66 (m, 1H),3.48-3.35 (m, 3H), 3.34- 3.27 (m, 1H), 3.24 (dd, J = 12.4, 7.2 Hz, 1H),2.60 (s, 3H), 2.35-2.23 (m, 1H), 1.96- 1.84 (m, 1H), 1.67-1.54 (m, 1H),1.43 (d, J = 6.7 Hz, 3H) 480

I-82 663.3 1.10 40-85% 15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.20 (br. s., 1H), 8.67 (s, 1H), 8.63 (br. s., 1H), 8.51 (s, 1H), 8.02(d, J = 8.5 Hz, 1H), 7.97-7.87 (m, 2H), 7.78 (s, 1H), 7.59 (d, J = 5.2Hz, 1H), 5.29 (br. s., 1H), 4.48- 4.23 (m, 3H), 4.06 (s, 3H), 3.96-3.84(m, 1H), 3.82-3.72 (m, 1H), 3.51-3.06 (m, 4H), 3.00-2.89 (m, 1H), 2.67(d, J = 9.8 Hz, 1H), 2.60 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H) 481

I-74 661.2 1.20 45-90% 25 min, 100% 6 min — 482

I-74 661.2 1.17 45-90% 25 min, 100% 6 min ¹H NMR (500 MHz, DMSO-d₆) δ10.09 (br. s., 1H), 8.70-8.65 (m, 1H), 8.60 (d, J = 6.7 Hz, 1H), 8.53(s, 1H), 8.07-7.90 (m, 3H), 7.79 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 5.13(br. s., 1H), 4.83 (br. s., 1H), 4.78-4.65 (m, 1H), 4.12-4.02 (m, 3H),3.73 (dd, J = 19.1, 11.7 Hz, 1H), 3.66- 3.51 (m, 1H), 3.46-3.35 (m, 3H),3.35- 3.17 (m, 1H), 2.66-2.59 (m, 3H), 2.35- 2.21 (m, 1H), 1.89 (br. s.,1H), 1.60 (d, J = 7.9 Hz, 1H), 1.41 (t, J = 5.0 Hz, 6H) 483

I-74 661.2 1.20 45-90% 25 min, 100% 6 min — 484

I-82 647.3 1.22 45-90% 15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.19 (br. s., 1H), 8.69 (s, 1H), 8.64 (br. s., 1H), 8.53 (s, 1H), 8.07-7.91 (m, 3H), 7.79 (s, 1H), 7.58-7.46 (m, 1H), 5.29 (br. s., 1H), 4.38(d, J = 8.9 Hz, 1H), 4.33-4.26 (m, 1H), 4.23 (d, J = 11.3 Hz, 1H), 4.07(s, 3H), 3.87 (d, J = 13.1 Hz, 1H), 3.67-3.38 (m, 2H), 3.16 (br. s.,1H), 3.06-2.94 (m, 1H), 2.83-2.71 (m, 1H), 2.61 (s, 3H), 1.94-1.81 (m,1H), 1.76 (br. s., 1H), 1.62 (br. s., 1H), 1.44 (d, J = 6.1 Hz, 4H),1.38 (d, J = 9.5 Hz, 1H) 485

I-82 647.3 1.22 45-90% 15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.19 (br. s., 1H), 8.69 (s, 1H), 8.63 (br. s., 1H), 8.53 (s, 1H), 8.07-7.90 (m, 3H), 7.79 (s, 1H), 7.59-7.46 (m, 1H), 5.29 (br. s., 1H), 4.38(d, J = 8.9 Hz, 1H), 4.33-4.17 (m, 1H), 4.12-4.01 (m, 3H), 3.88 (br. s.,1H), 3.68-3.53 (m, 1H), 3.16 (br. s., 1H), 3.01 (d, J = 7.6 Hz, 1H),2.77 (t, J = 10.5 Hz, 1H), 2.61 (s, 3H), 1.96-1.80 (m, 1H), 1.76 (br.s., 1H), 1.62 (br. s., 1H), 1.51-1.30 (m, 5H) 486

I-74 677.2 1.21 40-90% 19 min, 100% 5 min — 487

I-74 677.2 1.20 45-90% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.11 (br. s., 1H), 8.72 (s, 1H), 8.61 (br. s., 1H), 8.57 (d, J = 1.2Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.96 (d, J= 11.6 Hz, 1H), 7.83 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.14 (dd, J =6.4, 2.4 Hz, 1H), 4.81 (dd, J = 6.3, 2.6 Hz, 1H), 4.32 (br. s., 1H),4.16-3.98 (m, 4H), 3.97-3.85 (m, 1H), 3.82-3.40 (m, 3H), 2.63 (s, 3H),1.41 (dd, J = 6.3, 4.1 Hz, 6H). 488

I-82 663.3 1.21 40-100% 15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.21 (br. s., 1H), 8.73 (s, 1H), 8.62 (br. s., 1H), 8.56 (s, 1H),8.05-7.99 (m, 2H), 7.97 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 7.57 (d, J =8.5 Hz, 1H), 5.28 (dd, J = 8.9, 6.1 Hz, 1H), 4.88 (br. s., 1H),4.42-4.36 (m, 1H), 4.35-4.25 (m, 1H), 4.08 (s, 3H), 4.02 (d, J = 11.3Hz, 1H), 3.97-3.85 (m, 1H), 3.78 (d, J = 11.6 Hz, 1H), 3.70 (d, J = 6.7Hz, 1H), 3.57 (br. s., 1H), 3.50 (d, J = 13.4 Hz, 1H), 2.63 (s, 3H),1.44 (d, J = 6.4 Hz, 3H) 489

I-82 663.3 1.21 40-100% 15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.21 (br. s., 1H), 8.74 (s, 1H), 8.62 (br. s., 1H), 8.57 (s, 1H), 8.05-7.94 (m, 3H), 7.83 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 5.29 (dd, J = 9.2,6.1 Hz, 1H), 5.00-4.78 (m, 1H), 4.43-4.36 (m, 1H), 4.35-4.24 (m, 1H),4.16-3.99 (m, 4H), 3.98-3.85 (m, 1H), 3.82-3.66 (m, 1H), 3.66-3.42 (m,2H), 2.63 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H)

Example 490(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

To a solution Intermediate I-72B (150 mg, 0.334 mmol) in THF (6.5 mL)was added a 15% phosgene solution in toluene (2354 μl, 3.34 mmol). Theresulting slurry was allowed to stir overnight before concentrated downto a crude yellow residue. This intermediate chloroformate was retakenin THF (6.5 mL) and added dropwise to a premixed solution of2-methylpyrimidin-5-amine (39.9 mg, 0.365 mmol) and pyridine (0.134 mL,1.660 mmol) in THF (6.5 mL). After 10 min of stirring, the reactionmixture was concentrated and loaded directly onto an ISCO cartridge forpurification (40 g, 0-100% EtOAc/DCM, product at 85%) to afford Example490 (182 mg, 0.331 mmol, 94% yield) as a yellow solid. A small amount ofmaterial was purified by Prep HPLC for final characterization (Method D,50-100% over 10 min, hold 100% for 5 min). LC-MS: Method H, RT=1.17 min,MS (ESI) m/z: 585.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.76 (d, J=2.0 Hz,1H), 8.72 (br. s., 2H), 8.69 (s, 1H), 7.86-7.78 (m, 2H), 7.66 (t, J=71.8Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 6.49 (br. s., 1H), 5.21-5.12 (m, 1H),4.63 (dd, J=6.4, 3.3 Hz, 1H), 2.69 (s, 3H), 2.68 (s, 3H), 1.47 (d, J=6.6Hz, 3H), 1.44 (d, J=6.4 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −89.78 (s,3F), −132.17 (s, 1F).

Preparation of Substituted Quinoxalines

The substituted quinoxalines in the accompanying table were preparedaccording to the following general procedure, which is analogous to theprocedure used to synthesize Example 389.

To a solution of THF (0.05 M) and the appropriate alcohol (100 equiv)was added sodium hydride (60% by wt., 10 equiv). After the bubblingsubsided, a solution of Example 490 (1.0 equiv) in THF (0.05 M) wasadded dropwise. After 20 min of vigorous stirring at RT, the reactionmixture was quenched with a few drops of saturated NH₄Cl, diluted withEtOAc, filtered over Celite, concentrated and purified by Prep HPLC(Method D, unless otherwise indicated) to afford the desired example.

LCMS LCMS HPLC Ex. Quinox- [M + H]⁺ RT (Min) Prep No. Structure alinem/z Method H Method D NMR 491

490 577.2 1.31 75-100% 15 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ9.95 (br. s., 1H), 8.71 (br. s., 2H), 8.64 (s, 1H), 8.49 (s, 1H), 8.00(d, J = 7.9 Hz, 1H), 7.91 (d, J = 11.3 Hz, 1H), 7.73 (s, 1H), 5.09 (d, J= 6.4 Hz, 1H), 4.78 (d, J = 4.3 Hz, 1H), 4.39 (t, J = 6.6 Hz, 2H), 2.58(s, 3H), 2.50 (s, 3H-Buried under d-DMSO), 1.82 (sxt, J = 7.0 Hz, 2H),1.38 (m, 6H), 1.02 (t, J = 7.3 Hz, 3H) 492

490 577.2 1.30 75-100% 15 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ9.95 (br. s., 1H), 8.71 (br. s., 2H), 8.59 (s, 1H), 8.50 (s, 1H), 8.01(d, J = 8.2 Hz, 1H), 7.91 (d, J = 11.6 Hz, 1H), 7.75 (s, 1H), 5.45 (dt,J = 12.2, 6.1 Hz, 1H), 5.09 (d, J = 6.4 Hz, 1H), 4.78 (d, J = 4.3 Hz,1H), 2.59 (s, 3H), 2.50 (s, 3H-Buried under d-DMSO), 1.41 (d, J = 6.1Hz, 6H), 1.38 (m, 6H) 493

490 579.2 1.07 20-60% 20 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ8.67 (br. s., 2H), 8.63 (s, 1H), 8.47 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H),7.88 (d, J = 11.3 Hz, 1H), 7.71 (s, 1H), 5.04 (d, J = 6.1 Hz, 1H), 4.73(d, J = 4.3 Hz, 1H), 4.43 (d, J = 4.3 Hz, 2H), 3.77 (br. s., 2H), 2.55(s, 3H), 2.50 (s, 3H-Buried under d-DMSO), 1.33 (m, 6H)

Preparation of Alcohol Examples

The Alcohols in the accompanying table were prepared according to thefollowing two general procedures.

Primary Alcohols

A solution of the appropriately substituted hetero-aryl ester (1.0equiv) in THF (0.2 M) was cooled to −78° C. To this cooled reactionmixture was added DIBAl-H (1 M solution in toluene, 3.0 equiv) and thereaction mixture was to stirred at −78° C. for 1 hour. The reactionmixture was then quenched with saturated Rochelle's salt and allowed tostir for 2 h at room temperature. The resulting mixture was diluted withwater and extracted with EtOAc. The organic layer was washed with brine,dried with magnesium sulfate, filtered over a pad of silica gel andconcentrated. [Note: If crude NMR analysis of the isolated residueshowed a substantial amount of the intermediate aldehyde remaining, thenthe material was resubjected to the DIBAl-H conditions described abovein order to achieve complete reduction.] The crude material was purifiedby Prep HPLC (Method D, unless otherwise indicated) to afford thedesired example.

Tertiary Alcohols

A solution of the appropriately substituted hetero-aryl ester (1.0equiv) in THF (0.05 M) was cooled to −78° C. To this cooled reactionmixture was added methyl magnesium bromide (3.0 M solution in ether, 10equiv). The reaction mixture was allowed to warm to room temperature andstirred for 30 minutes at ambient temperature. The reaction mixture wasthen quenched with saturated ammonium chloride, diluted with water andextracted with EtOAc. The organic layer was washed with brine, driedwith magnesium sulfate, filtered over Celite and concentrated. Theresulting residue was purified by Prep HPLC (Method D, unless otherwiseindicated) to afford the desired example.

LCMS RT HPLC LCMS (Min) Prep Ex. [M + H]⁺ Method Method No. StructureEster m/z H D NMR 494

I-87  584.1, 586.1 1.05 70-95% 20 min, 100% 7 min ¹H NMR (500 MHz,DMSO-d₆) δ 10.27 (s, 1H), 8.76 (s, 1H), 8.61 (s, 1H), 8.33 (d, J = 5.5Hz, 1H), 8.05 (d, J = 7.3 Hz, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.38 (br.s., 1H), 5.35 (br. s., 1H), 4.54 (d, J = 5.2 Hz, 2H), 4.49-4.41 (m, 1H),4.39-4.32 (m, 1H), 4.14 (s, 3H), 2.70 (s, 3H), 1.49 (d, J = 6.1 Hz, 3H)495

I-83 550.2 0.99 40-80% 25 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.93 (br. s., 1H), 8.72 (s, 1H), 8.55 (s, 1H), 8.43 (d, J = 6.1 Hz,1H), 8.03-7.92 (m, 2H), 7.82 (s, 2H), 7.61 (d, J = 5.2 Hz, 1H), 5.32(br. s., 1H), 4.66 (s, 2H), 4.40 (d, J = 9.2 Hz, 1H), 4.29 (dd, J =10.8, 6.3 Hz, 1H), 4.07 (s, 3H), 3.90 (s, 1H), 2.62 (s, 3H), 1.45 (d, J= 6.4 Hz, 3H) 496

I-84 551.2 1.11 45-90% 25 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ8.91 (br. s., 2H), 8.77 (s, 1H), 8.60 (s, 1H), 8.09-7.98 (m, 2H), 7.87(s, 1H), 5.34 (d, J = 3.1 Hz, 1H), 4.60 (d, J = 4.9 Hz, 2H), 4.49-4.40(m, 1H), 4.34 (dd, J = 10.8, 6.0 Hz, 1H), 4.13 (s, 3H), 2.68 (s, 3H),1.50 (d, J = 6.4 Hz, 3H) 497

I-84 579.2 1.20 40-75% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ8.85 (br. s., 2H), 8.66 (s, 1H), 8.50 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H),7.92 (d, J = 11.6 Hz, 1H), 7.76 (s, 1H), 5.33-5.21 (m, 1H), 4.36 (dd, J= 10.7, 2.7 Hz, 1H), 4.30-4.23 (m, 1H), 4.05 (s, 3H), 2.59 (s, 3H), 1.45(s, 6H), 1.43 (d, J = 6.7 Hz, 3H) 498

I-82 578.2 1.03 70-100% 20 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ9.90 (br. s., 1H), 8.68 (s, 1H), 8.55-8.49 (m, 2H), 7.94 (t, J = 11.0Hz, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.56 (d, J = 8.5 Hz,1H), 5.25 (d, J = 3.4 Hz, 1H), 4.36-4.31 (m, 1H), 4.29-4.22 (m, 1H),4.05 (s, 3H), 2.59 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H), 1.39 (s, 6H) 499

I-74 564.1 1.03 30-90% 25 min 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ9.83 (br. s., 1H), 8.68 (s, 1H), 8.53 (br. s., 2H), 8.01 (d, J = 8.2 Hz,1H), 7.93 (d, J = 11.6 Hz, 1H), 7.84 (br. s., 1H), 7.79 (s, 1H), 7.36(d, J = 8.5 Hz, 1H), 5.09 (dd, J = 6.6, 2.6 Hz, 1H), 4.77 (d, J = 3.7Hz, 1H), 4.46 (s, 2H), 4.06 (s, 3H), 2.60 (s, 3H), 1.38 (m, 6H) 500

I-74 592.1 1.14 45-95% 12 min 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ9.82 (br. s., 1H), 8.69 (s, 1H), 8.56-8.48 (m, 2H), 8.02 (d, J = 8.2 Hz,1H), 7.94 (d, J = 11.6 Hz, 1H), 7.83 (br. s., 1H), 7.79 (s, 1H), 7.55(d, J = 8.5 Hz, 1H), 5.11 (d, J = 5.5 Hz, 1H), 4.79 (d, J = 6.1 Hz, 1H),4.07 (s, 3H), 2.61 (s, 3H), 1.43-1.37 (m, 12H) 501

I-86 593.2 1.27 40-90% 15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.06 (br. s., 1H), 8.83 (br. s., 2H), 8.69 (s, 1H), 8.54 (s, 1H), 8.03(d, J = 7.9 Hz, 1H), 7.94 (d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 5.13 (d, J= 4.3 Hz, 1H), 4.82 (d, J = 4.0 Hz, 1H), 4.07 (s, 3H), 2.61 (s, 3H),1.44 (s, 6H), 1.41 (m, 6H) 502

I-86 565.0 1.23 30-70% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ10.08 (br. s., 1H), 8.83 (br. s., 2H), 8.74 (s, 1H), 8.58 (s, 1H), 8.05(d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.6 Hz, 1H), 7.85 (s, 1H), 5.29 (t, J= 6.1 Hz, 1H), 5.13 (d, J = 5.8 Hz, 1H), 4.82 (br. s., 1H), 4.52 (d, J =6.1 Hz, 2H), 4.09 (s, 3H), 3.47 (br. s., 2H), 2.64 (s, 3H), 1.40 (m, 6H)

Preparation of Quinoxaline Examples

The quinoxalines in the accompanying table were prepared according tothe following general procedure, which is analogous to the proceduredescribed for Example 263. Thus, the appropriately substituted2-bromobenzothiazole (1.0 equiv), PdCl₂(dppf)-CH₂Cl₂ adduct (0.08equiv), and Intermediate I-9 (1.1 equiv) were solvated in a 3:1 mixtureof toluene and ethanol (0.05 M). A 2.0 M solution of aqueous sodiumcarbonate (9 equiv) was then added, and the mixture was degassed bybubbling argon through the solution for 10 min. The vial was then sealedunder an atmosphere of argon and heated to 105° C. thermally for 1 h.The resulting crude solution was diluted with EtOAc, filtered overCelite, concentrated, and purified by preparative HPLC (Method D, unlessotherwise indicated) to yield the desired example.

LCMS LCMS Ex. [M + H]⁺ RT (Min) HPLC Prep No. Structure Br-Bzt m/zMethod H Method D NMR 503

260A  341.9, 343.9 1.38 75-100% 25 min, 100% 4 min 1H NMR (500 MHz,DMSO-d₆) δ 8.78 (s, 1H), 8.68 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.92(s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.53-7.45 (m, 1H), 4.11 (s, 3H), 2.69(s, 3H) 504

256A 308.0 1.30 60-100% 18 min, 100% 10 min 1H NMR (500 MHz, DMSO-d₆) δ8.76 (s, 1H), 8.67 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 8.2Hz, 1H), 7.88 (s, 1H), 7.59 (t, J = 7.3 Hz, 1H), 7.53-7.47 (m, 1H), 4.10(s, 3H), 2.66 (s, 3H) 505

261A 322.0 1.40 80-100% 25 min, 100% 5 min 1H NMR (500 MHz, DMSO-d₆) δ8.76 (s, 1H), 8.67 (s, 1H), 7.99 (d, J = 3.7 Hz, 1H), 7.88 (s, 1H),7.42-7.34 (m, 2H), 4.10 (s, 3H), 2.81 (s, 3H), 2.67 (s, 3H) 506

93D  371.9, 373.9 1.37 60-100% 18 min, 100% 15 min 1H NMR (500 MHz,DMSO-d₆) δ 8.75 (s, 1H), 8.59 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 2.4Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 4.10 (s, 3H), 3.90 (s, 3H), 2.66 (s,3H) 507

268A  371.9, 373.9 1.37 60-100% 18 min, 100% 15 min 1H NMR (500 MHz,DMSO-d₆) δ 8.76 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.86(br. s., 2H), 4.10 (s, 3H), 3.98 (s, 3H), 2.65 (s, 3H) 509

I-3 351.9 1.37 60-100% 18 min, 100% 15 min 1H NMR (500 MHz, DMSO-d₆) δ8.74 (s, 1H), 8.60 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 7.01 (s, 1H),4.10 (s, 3H), 3.86 (s, 3H), 2.76 (s, 3H), 2.66 (s, 3H) 510

273A 326.0 1.32 65-100% 25 min, 100% 4 min 1H NMR (500 MHz, DMSO-d₆) δ8.78 (s, 1H), 8.68 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H),7.55-7.48 (m, 1H), 7.45-7.38 (m, 1H), 4.11 (s, 3H), 2.67 (s, 3H)

Preparation of Quinoline Examples

The Quinolines in the accompanying table were prepared according to thefollowing general procedure, which is analogous to the proceduredescribed for Example 263. Thus, Intermediate I-88 (1.0 equiv),PdCl₂(dppf)-CH₂Cl₂ adduct (0.08 equiv), and the appropriatelysubstituted quinoline (1.1 equiv) were solvated in a 3:1 mixture oftoluene and ethanol (0.05 M). A 2.0 M solution of aqueous sodiumcarbonate (9 equiv) was added, and the mixture was degassed by bubblingargon through the solution for 10 min. The vial was then sealed thensealed under an atmosphere of argon and thermally heated to 105° C. 1 h.The crude solution was diluted with EtOAc, filtered over Celite,concentrated and purified by preparative HPLC (Method D, unlessotherwise indicated) to yield the desired example.

LCMS RT HPLC LCMS (Min) Prep Ex. [M + H]⁺ Method Method No. StructureQuin m/z H D NMR 512

I-121  614.0, 616.1 1.14 40-90% 20 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.76 (br. s., 1H), 8.58 (d, J = 2.4 Hz, 3H), 8.34 (d, J = 1.8Hz, 1H), 7.91 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 11.6 Hz,1H), 7.66 (d, J = 2.1 Hz, 1H), 5.13-5.03 (m, 1H), 4.74 (d, J = 3.7 Hz,1H), 4.21 (t, J = 4.6 Hz, 2H), 3.88 (s, 2H), 1.43-1.31 (m, 6H) 513

I-126  628.0, 629.9 1.19 50-100% 25 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.80 (br. s., 1H), 8.83 (d, J = 2.4 Hz, 1H), 8.61 (br. s.,3H), 8.16 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.3 Hz, 1H),7.90 (br. s., 1H), 5.10 (d, J = 6.4 Hz, 1H), 4.81 (d, J = 6.1 Hz, 1H),4.32-4.17 (m, 4H), 3.68 (d, J = 4.6 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H),1.43-1.32 (m, 6H) 514

I-124 594.1 1.03 40-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ9.81 (br. s., 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.60 (br. s., 3H), 8.02 (d,J = 8.2 Hz, 1H), 7.94 (d, J = 11.3 Hz, 1H), 7.87 (d, J = 6.1 Hz, 2H),5.09 (d, J = 6.4 Hz, 1H), 4.80 (d, J = 3.4 Hz, 1H), 4.23 (d, J = 4.6 Hz,2H), 3.99 (s, 3H), 3.69 (d, J = 4.3 Hz, 2H), 2.61 (s, 3H), 1.39 (d, J =6.1 Hz, 6H) 515

I-124 650.,  652.0 1.14 50-90% 23 min, 100% 5 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.81 (br. s., 1H), 9.06 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H),8.61 (br. s., 2H), 8.35 (d, J = 5.2 Hz, 2H), 8.07 (d, J = 7.9 Hz, 1H),7.98 (d, J = 11.6 Hz, 1H), 7.51 (t, J = 74.2 Hz, 1H), 5.11 (d, J = 6.1Hz, 1H), 4.83 (d, J = 4.3 Hz, 1H), 4.24 (t, J = 4.9 Hz, 2H), 3.69 (d, J= 4.9 Hz, 2H), 1.45-1.36 (m, 6H)

Example 5161-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-methoxypropan-2-ylpyridin-3-ylcarbamate (rac)

Intermediate 516A:1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-methoxypropan-2-ol

To a suspension of Intermediate I-64 (15 mg, 0.044 mmol) andtetrabutylammonium bromide (28.3 mg, 0.088 mmol) in THF (1 mL) was addedpotassium hydroxide (0.33 M in H₂O) (0.200 mL, 0.066 mmol) followed byracemic 2-(methoxymethyl)oxirane (38.7 mg, 0.439 mmol). The mixture wasthen sealed and heated to 65° C. overnight. After 15 h, the reaction wasquenched with saturated NaHCO₃ and diluted with EtOAc. The organic phasewas washed with brine, dried over MgSO₄, filtered over Celite,concentrated and purified by ISCO (4 g, 0-60% EtOAc/Hexanes, 16 min.Product at 40%) to afford Intermediate 516A (11 mg, 0.026 mmol, 58.3%yield) as a yellow solid. LC-MS: Method H, RT=1.09 min, MS (ESI) m/z:430.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J=1.8 Hz, 1H), 8.53 (s,1H), 7.80 (d, J=11.2 Hz, 1H), 7.74 (d, J=0.9 Hz, 1H), 7.48 (d, J=7.9 Hz,1H), 4.26 (quin, J=5.2 Hz, 1H), 4.21-4.16 (m, 2H), 4.12 (s, 3H),3.69-3.57 (m, 2H), 3.45 (s, 3H), 3.43 (d, J=6.6 Hz, 1H), 2.64 (s, 3H).

Example 516 (Rac)

To a solution of Intermediate 516A (10 mg, 0.023 mmol) in THF (1 mL) wasadded 15% phosgene in toluene (0.164 mL, 0.233 mmol) at roomtemperature. The reaction mixture was allowed to stir overnight. After16 h, the reaction mixture was concentrated to afford the desiredchloroformate intermediate as a crude yellow residue. This crudematerial was retaken in THF (1 mL) and added dropwise to a pre-mixedsolution of pyridin-3-amine (4.38 mg, 0.047 mmol) and pyridine (0.019mL, 0.232 mmol) After 5 min of stirring, the reaction mixture wasconcentrated and purified by prep HPLC (Method C, 20-60% over 20 min,hold 100% for 5 min) to afford Example 516 (10.5 mg, 0.023 mmol, 78%yield) as a yellow solid. LC-MS: Method H, RT=0.94 min, MS (ESI) m/z:550.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.41 (br. s., 1H), 8.81 (br.s., 1H), 8.67 (s, 1H), 8.51 (s, 1H), 8.37 (d, J=4.4 Hz, 1H), 8.12 (d,J=7.9 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.93 (d, J=11.5 Hz, 1H), 7.77 (s,1H), 7.60 (dd, J=8.4, 5.0 Hz, 1H), 5.37 (d, J=4.6 Hz, 1H), 4.50-4.43 (m,1H), 4.43-4.36 (m, 1H), 4.07 (s, 3H), 3.82-3.72 (m, 2H), 3.37 (s, 3H),2.61 (s, 3H).

Example 517(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ylpyridin-3-ylcarbamate

Intermediate 517A:(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ol

This intermediate was prepared in a manner analogous to Intermediate516A. Thus, Intermediate I-64 was reacted with (R)-2-ethyloxirane toafford Intermediate 517A (77% yield) as a yellow solid. LC-MS: Method H,RT=1.14 min, MS (ESI) m/z: 414.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.59(d, J=2.0 Hz, 1H), 8.53 (s, 1H), 7.81 (d, J=11.4 Hz, 1H), 7.74 (s, 1H),7.45 (d, J=7.9 Hz, 1H), 4.16-4.09 (m, 4H), 4.08-3.95 (m, 2H), 2.64 (s,3H), 2.44 (d, J=3.7 Hz, 1H), 1.74-1.63 (m, 2H), 1.07 (t, J=7.5 Hz, 3H).

Example 517

This intermediate was prepared in a manner analogous to Example 516.Thus, Intermediate 517A was reacted with phosgene followed bypyridin-3-amine. The crude reaction residue was purified by Prep HPLC(Method D, 55-100% over 20 min, hold 100% for 5 min) to afford Example517 (68% yield) as a yellow solid. LC-MS: Method H, RT=0.97 min, MS(ESI) m/z: 534.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J=2.0 Hz,1H), 8.53 (s, 1H), 7.81 (d, J=11.4 Hz, 1H), 7.74 (s, 1H), 7.45 (d, J=7.9Hz, 1H), 4.16-4.09 (m, 4H), 4.08-3.95 (m, 2H), 2.64 (s, 3H), 2.44 (d,J=3.7 Hz, 1H), 1.74-1.63 (m, 2H), 1.07 (t, J=7.5 Hz, 3H).

Example 5184-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-N-(pyridin-3-yl)butanamide

Intermediate 518A: tert-butyl4-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butanoate

To a solution of Intermediate I-65 (100 mg, 0.266 mmol) in DMF (1330 μl)was added tert-butyl 4-bromobutanoate (89 mg, 0.399 mmol) followed bypotassium carbonate (73.6 mg, 0.532 mmol). The reaction vessel wassealed and the red colored solution was heated to 65° C. After 2 h, thereaction mixture was cooled to room temperature and quenched with a fewdrops of AcOH. The resulting mixture was diluted with EtOAc, filteredover Celite and concentrate in vacuo to afford crude Intermediate 518A,which was telescoped into the next reaction without purification. LC-MS:Method H, RT=1.43 min, MS (ESI) m/z: [Not observed](M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.66 (s, 1H), 8.44 (s, 1H), 7.69 (br. s., 1H), 7.29 (d,J=7.5 Hz, 1H), 4.19-4.04 (m, 5H), 2.63 (s, 3H), 2.58-2.44 (m, 2H), 2.15(dq, J=12.8, 6.4 Hz, 2H), 1.45 (s, 9H).

Intermediate 518B:4-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butanoic acid

To a solution of crude Intermediate 518A (138 mg, 0.266 mmol) in DCM(2664 μl) was added TFA (2664 μl). The resulting solution immediatelybecame dark red in color. After stirring at room temperature for 30 min,the reaction mixture was concentrated in vacuo to afford crudeIntermediate 518B, which was telescoped into the next reaction withoutpurification. LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 462.1, 464.1(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.69 (d, J=1.8 Hz, 1H), 8.49 (s, 1H),7.75-7.70 (m, 1H), 7.33 (d, J=7.3 Hz, 1H), 4.16-4.10 (m, 5H), 2.65 (s,3H), 2.47 (t, J=7.4 Hz, 2H), 2.04-1.93 (m, 2H).

Example 518

To a brown suspension crude Intermediate 518B (15 mg, 0.032 mmol) in DMF(1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.034 mL, 0.195mmol) followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (50% in DMF) (0.058 mL, 0.097 mmol). The reaction mixturewas stirred at room temperature for 2, then pyridin-3-amine (9.17 mg,0.097 mmol) was added. After an additional 10 min of stirring, thereaction mixture was concentrated and purified by prep HPLC (Method D,50-100% over 15 min, hold 100% for 7 min) to afford Example 518 (3.3 mg,0.006 mmol, 18% yield) as a yellow solid over the three step sequence.LC-MS: Method H, RT=1.06 min, MS (ESI) m/z: 538.2, 540.2 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 10.27 (s, 1H), 8.79 (br. s., 1H), 8.74 (s, 1H),8.59 (s, 1H), 8.27 (d, J=4.3 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.99 (d,J=7.3 Hz, 1H), 7.85 (s, 1H), 7.39 (dd, J=8.2, 4.6 Hz, 1H), 4.26 (t,J=6.1 Hz, 2H), 4.08 (s, 3H), 2.65 (s, 3H), 2.60 (t, J=7.3 Hz, 2H), 2.15(t, J=6.6 Hz, 2H).

Example 5191-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-3-(pyridin-3-yl)urea

Intermediate 519A: tert-butyl(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)carbamate

To a dark red solution of Intermediate I-65 (85 mg, 0.226 mmol) andcesium carbonate (221 mg, 0.679 mmol) in DMF (2262 μl) was addedtert-butyl (2-bromoethyl)carbamate (76 mg, 0.339 mmol) as a cold solidfrom the freezer [Note: did not allow reagent to melt]. The reactionmixture was sealed and heated to 65° C. After 1 h of heating, thereaction was quenched with 0.3 mL AcOH, diluted with EtOAc, filteredover Celite and concentrated to a dark yellow solid. The crude materialwas purified by ISCO (12 g, 0-20% EtOAc/DCM, 16 min.) to affordIntermediate 519A (81 mg, 0.156 mmol, 69.0% yield) as a yellow solid.LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 519.2, 521.2 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.65 (d, J=1.8 Hz, 1H), 8.43 (s, 1H), 7.69 (dd,J=2.0, 0.9 Hz, 1H), 7.26 (d, J=6.4 Hz, 1H), 5.17 (br. s., 1H), 4.17-4.15(m, 2H), 4.10 (s, 3H), 3.63 (d, J=5.3 Hz, 2H), 2.63 (s, 3H), 1.48 (s,9H).

Intermediate 519B:2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethanamine, TFA

To a suspension of Intermediate 519A (40 mg, 0.077 mmol) in DCM (2 mL)was added TFA (1.0 mL). The resulting solution immediately became brightred in color. After stirring at room temperature for 15 min, thereaction mixture was concentrated in vacuo to afford crude Intermediate519B (41.1 mg, 0.077 mmol, 100% yield). This material was telescopedinto subsequent reactions without further purification. LC-MS: Method H,RT=0.95 min, MS (ESI) m/z: 419.4, 421.4 (M+H)⁺.

Example 519

To a solution of Intermediate 519B (20 mg, 0.038 mmol) in THF (2 mL) wasadded diisopropylethylamine (0.13 mL, 0.75 mmol) followed by3-isocyanatopyridine (13.52 mg, 0.113 mmol) at room temperature. After15 h, the reaction mixture was concentrated and purified by prep HPLC(Method D, 45-95% over 15 min, hold 100% for 5 min) to afford Example519 (1.2 mg, 0.002 mmol, 6% yield) as a yellow solid over the two stepsequence. LC-MS: Method H, RT=0.98 min, MS (ESI) m/z: 539.1, 541.1(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.71 (s, 1H), 8.56 (s,1H), 8.54 (s, 1H), 8.11 (d, J=4.6 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.88(d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.26 (dd, J=8.4, 4.7 Hz, 1H), 6.64-6.56(m, 1H), 4.24 (t, J=5.0 Hz, 2H), 4.07 (s, 3H), 3.59 (d, J=5.5 Hz, 2H),2.63 (s, 3H).

Example 5201-(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)-1-methyl-3-(2-methylpyrimidin-5-yl)urea

Intermediate 520A: tert-butyl(2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl)(methyl)carbamate

To a suspension of Intermediate 519A (43 mg, 0.083 mmol) in THF (1 mL)was added sodium hydride (9.94 mg, 0.249 mmol). The bright red solutionwas stirred at room temperature for 5 min before methyl iodide (2.0 M inMTBE) (0.207 mL, 0.414 mmol) was added. The reaction was then allowed tostir overnight before being quenched with AcOH, concentrated, and loadeddirectly onto an ISCO cartridge for purification (12 g, 0-50%EtOAc/Hexanes, 16 min. Product at 25%) to afford Intermediate 520A (24mg, 0.045 mmol, 54.3% yield) as a yellow solid. LC-MS: Method H, RT=1.37min, MS (ESI) m/z: 533.1, 535.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.73(d, J=1.8 Hz, 1H), 8.54 (s, 1H), 7.77 (d, J=0.7 Hz, 1H), 7.37 (d, J=7.0Hz, 1H), 4.25 (d, J=17.6 Hz, 2H), 4.13 (s, 3H), 3.74-3.66 (m, 2H), 3.05(s, 3H), 2.66 (s, 3H), 1.48 (s, 9H).

Intermediate 520B:2-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-N-methylethanamine,TFA

To a suspension of Intermediate 520A (24 mg, 0.045 mmol) in DCM (2 mL)was added TFA (1.0 mL). The resulting solution immediately became brightred in color. After stirring for 20 min at room temperature, thereaction mixture was concentrated in vacuo to afford crude Intermediate520B (24.63 mg, 0.045 mmol, 100% yield). This material was telescopedinto the subsequent reactions without further purification. LC-MS:Method H, RT=0.92 min, MS (ESI) m/z: 433.0, 435.0 (M+H)⁺.

Example 520

To a mixture of crude Intermediate 520B (12 mg, 0.022 mmol) and DIPEA(0.057 mL, 0.329 mmol) in THF (1 mL) was added 15% phosgene in toluene(0.108 mL, 0.154 mmol) at room temperature. The solution immediatelybecame smoky and deposited white salts. After 10 min,2-methylpyrimidin-5-amine (7.18 mg, 0.066 mmol) and silver nitrate(18.64 mg, 0.110 mmol) were added. The reaction mixture was then sealedand heated to 65° C. for 1 h. The resulting reaction mixture was cooledto room temperature, diluted with EtOAc, filtered over Celite,concentrated and purified by prep HPLC (Method D, 40-75% over 25 min,hold 100% for 7 min) to afford Example 520 (1.1 mg, 0.002 mmol, 8%yield) as a yellow solid over the two step sequence. LC-MS: Method H,RT=1.15 min, MS (ESI) m/z: 568.3, 570.2 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.76 (s, 2H), 8.69 (s, 1H), 8.55 (s, 1H), 7.95 (d, J=7.3 Hz,1H), 7.81 (s, 1H), 4.34 (br. s., 2H), 4.07 (s, 3H), 3.81 (br. s., 2H),3.11 (s, 3H), 2.63 (s, 3H), 2.52 (s, 3H).

Example 521(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (6-(morpholinomethyl)pyridin-3-yl)carbamate

To a solution of Example 426 (9 mg, 0.014 mmol) in THF (1 mL) was addeddiacetoxyzinc (5.11 mg, 0.028 mmol) followed by triethoxysilane (0.026mL, 0.139 mmol). The resulting mixture was sealed and heated to 65° C.overnight. The resulting reaction mixture was diluted with EtOAc, washedwith brine, dried over MgSO₄, filtered and purified by prep HPLC (MethodD, 45-100% over 20 min, hold 100% for 6 min) to afford Example 521 (1.4mg, 0.002 mmol, 14% yield) as a yellow solid. LC-MS: Method H, RT=1.07min, MS (ESI) m/z: 633.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.94-9.68(m, 1H), 8.67 (s, 1H), 8.51 (s, 2H), 7.98 (d, J=8.2 Hz, 1H), 7.90 (d,J=11.6 Hz, 1H), 7.78 (s, 2H), 7.29 (br. s., 1H), 5.04 (d, J=5.8 Hz, 1H),4.73 (br. s., 1H), 4.01 (s, 3H), 3.52 (br. s., 2H) [note: morpholineprotons appear to under-integrate], 2.56 (s, 3H), 1.32 (m, 6H).

Example 522(2R,3S)-3-((2-(2-(dimethylamino)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

To a vial containing Intermediate I-73 (10 mg, 0.017 mmol) was addeddimethylamine (2 M in THF) (1 mL, 2.000 mmol) followed by 2-propanol (1mL). The vial was sealed and heated to 65° C. After 6 h of heating thereaction mixture was concentrated, and purified by prep HPLC (Method D,40-80% over 20 min, hold 100% for 5 min) to afford Example 522 (7.8 mg,0.014 mmol, 80% yield) as a yellow solid. LC-MS: Method H, RT=1.07 min,MS (ESI) m/z: 562.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.98 (br. s.,1H), 8.76 (s, 1H), 8.74 (br. s., 2H), 8.30 (s, 1H), 8.01 (d, J=8.2 Hz,1H), 7.94 (d, J=11.3 Hz, 1H), 7.57 (s, 1H), 5.11 (d, J=6.1 Hz, 1H), 4.83(d, J=6.4 Hz, 1H), 3.27 (br. s., 6H), 2.55 (br. s., 3H), 1.40 (br. s.,6H).

Example 5235-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)picolinicacid, TFA

To a solution of Intermediate I-74 (8.5 mg, 0.015 mmol) in THF (1 mL)was added lithium hydroxide (1 M) (0.2 mL, 0.200 mmol). The reactionmixture was sealed and heated to 65° C. After 1 h, the reaction mixturewas quenched with 1 M HCl, diluted with EtOAc, extracted, concentrated,and purified by prep HPLC (Method C, 30-100% over 20 min, hold 100% for5 min) to afford Example 523 (4.6 mg, 0.008, 54% yield) as a yellowsolid. LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 578.1 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.77 (br. s., 1H), 8.72 (s, 1H), 8.57 (s, 1H),8.11-8.01 (m, 3H), 7.98 (d, J=11.6 Hz, 1H), 7.84 (s, 1H), 5.20 (d, J=6.4Hz, 1H), 4.87 (d, J=4.3 Hz, 1H), 4.13 (s, 3H), 2.66 (s, 3H), 1.47 (t,J=6.3 Hz, 6H).

Example 524(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl carbamate

To a solution Intermediate I-72 (85 mg, 0.206 mmol) in THF (4112 μl) wasadded 15% phosgene in toluene (1450 μl, 2.056 mmol). The resultingslurry was allowed to stir overnight before being concentrated down to acrude yellow residue. This chloroformate intermediate was retaken in THF(1 mL) and added dropwise to a separate vial containing a solution ofammonia (0.5 M in dioxane) (0.420 mL, 0.210 mmol). After 5 min ofstirring at RT, the reaction mixture was concentrated and purified byprep HPLC (Method D, 45-80% over 30 min, hold 100% for 8 min) to affordExample 524 (5.7 mg, 0.012 mmol, 59% yield) as a yellow solid. LC-MS:Method H, RT=1.10 min, MS (ESI) m/z: 457.3 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.74 (s, 1H), 8.59 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.98 (d,J=11.3 Hz, 1H), 7.85 (s, 1H), 6.63 (br. s., 2H), 4.95 (dd, J=6.3, 3.2Hz, 1H), 4.71 (dd, J=6.1, 3.4 Hz, 1H), 4.13 (s, 3H), 2.67 (s, 3H), 1.40(d, J=6.4 Hz, 3H), 1.34 (d, J=6.4 Hz, 3H).

Example 5251-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)-3-isobutoxypropan-2-yl(2-methylpyrimidin-5-yl)carbamate (rac)

This example was prepared in a manner analogous to Example 379 above.Thus, reaction of Intermediate 379A with 2-methylpyrimidin-5-amineafforded Example 525 (rac) in 76% yield following purification bypreparative HPLC (Method C, 60-95% over 25 min, hold at 100% for 10min). LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 607.1 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 10.17 (br. s., 1H), 8.76 (br. s., 2H), 8.72 (s,1H), 8.56 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.97 (d, J=11.6 Hz, 1H), 7.82(s, 1H), 5.33 (br. s., 1H), 4.50-4.43 (m, 1H), 4.43-4.36 (m, 1H), 4.09(s, 3H), 3.78 (d, J=5.2 Hz, 2H), 3.42-3.20 (m, 2H), 2.63 (s, 3H), 1.82(dt, J=13.4, 6.7 Hz, 1H), 0.86 (d, J=6.4 Hz, 6H).

Example 526(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-(2-hydroxyethyl)pyridin-3-yl)carbamate

To a solution of Intermediate I-80 (300 mg, 0.702 mmol) in THF (1.4 mL,0.05 M) was added 15% phosgene in toluene (4949 μl, 7.02 mmol). Theresulting slurry was allowed to stir overnight. After 16 h, the reactionmixture was concentrated down to a yellow residue. This crudechloroformate intermediate was retaken in THF (2 mL) and slowly added toa premixed solution of Intermediate I-109 (33.5 mg, 0.133 mmol) andpyridine (0.083 mL, 1.021 mmol) in THF (2 mL). After 5 min of stirringat room temperature, the reaction mixture was concentrated to removeexcess pyridine and then retaken in THF (2 mL). To this mixture wasadded TBAF (1 M in THF) (0.306 mL, 0.306 mmol), and the resultingsolution was stirred at room temperature for 6 h. The resulting mixturewas concentrated and purified by prep HPLC (Method D, 50-100% over 20min, hold 100% for 5 min) to afford Example 526 (31.4 mg, 0.051 mmol,50% yield) as a yellow solid. LC-MS: Method H, RT=1.06 min, MS (ESI)m/z: 592.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.81 (br. s., 1H), 8.73(s, 1H), 8.60 (s, 1H), 8.58 (br. s., 1H), 8.09 (d, J=8.2 Hz, 1H), 8.00(d, J=11.6 Hz, 1H), 7.87-7.78 (m, 1H), 7.23 (d, J=8.5 Hz, 1H), 5.16 (d,J=6.4 Hz, 1H), 4.83 (d, J=4.0 Hz, 1H), 4.67 (t, J=5.0 Hz, 1H), 4.58 (q,J=7.0 Hz, 2H), 3.74 (q, J=6.2 Hz, 2H), 2.85 (t, J=6.9 Hz, 2H), 2.67 (s,3H), 1.50 (t, J=7.0 Hz, 3H), 1.45 (t, J=7.5 Hz, 6H).

Example 527(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate

The following example was prepared in a manner analogous to the generalhindered amide procedure described in the table above. Thus,Intermediate I-89 was reacted with 1-amino-2-methylpropan-2-ol (100equiv) and magnesium chloride (10 equiv) to afford Example 527 in 36%yield following purification by preparative HPLC (Method D, 45-90% over20 min, hold at 100% for 8 min). LC-MS: Method H, RT=1.27 min, MS (ESI)m/z: 663.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.23 (br. s., 1H), 8.73(s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.35 (t, J=6.1 Hz, 1H), 8.12-8.05(m, 2H), 8.04-7.98 (m, 2H), 7.84 (s, 1H), 5.19 (dd, J=6.6, 2.6 Hz, 1H),4.92-4.85 (m, 1H), 4.81 (s, 1H), 4.59 (q, J=7.0 Hz, 2H), 3.33-3.27 (m,2H), 2.68 (s, 3H), 1.50 (t, J=7.2 Hz, 3H), 1.47 (t, J=5.8 Hz, 6H), 1.15(s, 6H).

Example 528(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate

Intermediate I-86 (55 mg, 0.093 mmol) was solvated in THF (1 mL) andcooled to −78° C. To this mixture was added DIBAl-D (0.7 M in toluene)(0.398 mL, 0.278 mmol). After 1 h of stirring at −78° C., the reactionmixture was quenched with 1 mL of a 1 M HCl solution at −78° C. Theresulting mixture was allowed to thaw to room temperature and stirredfor a total of 30 min until the solution became fluid and bright yellow.The reaction mixture was then diluted with EtOAc and washed withsaturated NH₄Cl before being dried over MgSO₄ and filtered over a pad ofSiO₂ gel to remove aluminates. The resulting filtrate was concentratedand resubjected to the reduction conditions above to push any remainingdeutero-aldehyde intermediate to the desired deutero-alcohol product.Following a repeat of the previous work-up procedure, the crude productwas purified by prep HPLC (Method D, 35-100% over 20 min, hold 100% for5 min) to afford Example 528 (16.3 mg, 0.028 mmol, 30% yield) as ayellow solid. LC-MS: Method H, RT=1.11 min, MS (ESI) m/z: 567.1 (M+H)⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.80 (br. s., 2H), 8.68 (s, 1H), 8.53 (s,1H), 8.00 (d, J=8.2 Hz, 1H), 7.92 (d, J=11.6 Hz, 1H), 7.80 (s, 1H),5.16-5.04 (m, 1H), 4.80 (d, J=3.4 Hz, 1H), 4.48 (d, J=5.5 Hz, 1H), 4.06(s, 3H), 2.60 (s, 3H), 1.38 (t, J=5.8 Hz, 6H).

Example 529(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate

The following example was made in a manner analogous to the primaryalcohol procedure described in the table above. Thus, Intermediate I-90was reacted with DIBAl-H to afford Example 529 in 53% yield followingpurification by preparative HPLC (Method D, 50-100% over 21 min, hold at100% for 6 min). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z: 579.2(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.82 (br. s., 2H), 8.69 (s, 1H),8.55 (s, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.95 (d, J=11.6 Hz, 1H), 7.81 (s,1H), 5.13 (d, J=4.0 Hz, 1H), 4.81 (d, J=4.0 Hz, 1H), 4.59-4.47 (m, 4H),2.63 (s, 3H), 1.45 (t, J=7.0 Hz, 3H), 1.40 (t, J=5.5 Hz, 6H).

Example 530(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl(6-((2-methyl-2-(phosphonooxy)propyl)carbamoyl)pyridin-3-yl)carbamate,TFA

Intermediate 530A:(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)(Boc)carbamate

To a solution of Example 448 (55 mg, 0.087 mmol) in THF (5 mL) was addedDMAP (26.5 mg, 0.217 mmol) followed by BOC-Anhydride (0.024 mL, 0.104mmol). After 30 min of stirring at room temperature, the reaction wasquenched with methanol, concentrated and purified by ISCO (12 g, 0-100%EtOAc/Hex, Product at 75%) to afford Intermediate 530A (52 mg, 0.071mmol, 82% yield) as a yellow foaming solid. LC-MS: Method H, RT=1.22min, MS (ESI) m/z: 735.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d,J=1.8 Hz, 1H), 8.54 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.24 (t, J=6.2 Hz,1H), 8.17 (d, J=8.1 Hz, 1H), 7.83 (d, J=11.4 Hz, 1H), 7.75 (dd, J=1.8,0.9 Hz, 1H), 7.65 (dd, J=8.1, 2.4 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H),5.42-5.31 (m, 1H), 4.16-4.08 (m, 5H), 3.99 (dd, J=10.3, 6.8 Hz, 1H),3.48-3.40 (m, 1H), 3.37-3.29 (m, 1H), 2.64 (s, 3H), 2.04 (s, 1H), 1.42(s, 9H), 1.38 (d, J=6.4 Hz, 3H), 1.24 (s, 3H), 1.21 (s, 3H).

Intermediate 530B:(R)-1-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)propan-2-yl(6-((2-((bis(2-(trimethylsilyl)ethoxy)phosphoryl)oxy)-2-methylpropyl)carbamoyl)pyridin-3-yl)(Boc)carbamate

To a solution of Intermediate 530A (20 mg, 0.027 mmol) and 1H-tetrazole(9.53 mg, 0.136 mmol) in DCM (1 mL) was addedbis(2-(trimethylsilyl)ethyl) diisopropylphosphoramidite (49.8 mg, 0.136mmol). The reaction mixture was sealed and heated to 50° C. for 30 min.After the desired phosphite intermediate was formed (monitored by TLC),the resulting solution was cooled to room temperature and hydrogenperoxide (35% wt. in H₂O) (0.119 mL, 1.361 mmol) was added. After 20 minof additional stirring, the crude phosphate was diluted with EtOAc, andwashed with saturated Na₂S₂O₃. The organic phase was dried over MgSO₄,filtered over Celite and concentrated to give Intermediate 530B (27.6mg, 0.027 mmol, 100% yield) as a yellow oil. Quantitative yield wasassumed and the crude intermediate was telescoped into the next reactionwithout further purification. LC-MS: Method H, RT=1.55 min, MS (ESI)m/z: 1015.4 (M+H)⁺.

Example 530

To a solution of crude Intermediate 530B (28 mg, 0.028 mmol) in DCM (2mL) was added TFA (1.0 mL) at room temperature. After 10 min ofstirring, the reaction mixture was concentrated and purified by PrepHPLC (Method C, 50-100% over 10 min, hold 100% for 5 min) to affordExample 530 (7.4 mg, 0.009 mmol, 31% yield) as a yellow TFA salt overthe three step sequence. LC-MS: Method H, RT=1.09 min, MS (ESI) m/z:715.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s, 1H), 8.69 (s, 1H),8.67-8.59 (m, 2H), 8.52 (d, J=1.5 Hz, 1H), 8.07-8.00 (m, 1H), 7.98-7.88(m, 3H), 7.78 (d, J=0.9 Hz, 1H), 5.22 (td, J=6.2, 3.2 Hz, 1H), 4.37-4.29(m, 1H), 4.27-4.17 (m, 1H), 4.02 (s, 3H), 3.49 (d, J=5.1 Hz, 2H), 2.56(s, 3H), 1.37 (d, J=6.6 Hz, 3H), 1.27 (s, 6H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −73.51, −134.32.

Example 531(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate, TFA

Intermediate I-89 (70 mg, 0.116 mmol) was solvated in THF (1.156 mL) and(S)-1-aminopropan-2-ol (0.12 mL, 1.524 mmol) was added to the solution.The reaction vial was sealed and heated to 65° C. After 18 h of heating,the reaction mixture was concentrated and purified by prep HPLC (MethodC, 50-100% over 19 min, hold 100% for 10 min) to afford Example 531 (55mg, 0.070 mmol, 61% yield) as a yellow solid. LC-MS: Method H, RT=1.27min, MS (ESI) m/z: 649.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.16 (br.s., 1H), 8.67 (s, 1H), 8.63 (s, 1H), 8.52 (s, 1H), 8.42 (t, J=5.8 Hz,1H), 8.07-7.98 (m, 2H), 7.98-7.89 (m, 2H), 7.76 (s, 1H), 5.13 (d, J=4.0Hz, 1H), 4.82 (d, J=5.2 Hz, 1H), 4.52 (q, J=7.0 Hz, 2H), 3.82-3.72 (m,1H), 3.48 (br. s., 1H), 3.37-3.26 (m, 1H), 3.18-3.08 (m, 1H), 2.61 (s,3H), 1.47-1.42 (m, 3H), 1.41 (t, J=5.8 Hz, 6H), 1.05 (d, J=6.1 Hz, 3H).

Example 532(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-((phosphonooxy)methyl)pyrimidin-5-yl)carbamate

Intermediate 532A:(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(((bis(2-(trimethylsilyl)ethoxy)phosphoryl)oxy)methyl)pyrimidin-5-yl)carbamate

To a solution of Example 529 (20 mg, 0.035 mmol) and 1H-tetrazole (24.21mg, 0.346 mmol) in DCM (3457 μl) was added bis(2-(trimethylsilyl)ethyl)diisopropylphosphoramidite (126 mg, 0.346 mmol) at room temperature.After 1 h, the reaction mixture was cooled to 0° C. and hydrogenperoxide (35% wt. in H₂O) (90.8 μl, 1.037 mmol) was added. The resultingmixture was allowed to thaw to room temperature and stirred vigorouslyfor 30 min. The reaction mixture was then diluted with EtOAc and washedwith saturated Na₂S₂O₃. The organic phase was dried over MgSO₄, filteredover Celite and concentrated to give Intermediate 532A (29.7 mg, 0.035mmol, 100% yield) as a yellow oil mixed with excess phosphate reagent.Quantitative yield was assumed, and the crude intermediate wastelescoped into the next reaction without further purification. LC-MS:Method H, RT=1.52 min, MS (ESI) m/z: 859.5 (M+H)⁺.

Example 532

Crude Intermediate 532A (29 mg, 0.034 mmol) was solvated in DCM (2 mL).TFA (0.500 mL) was added causing the solution to turn dark yellow andbubble vigorously. After 10 min, the reaction mixture was concentratedand purified by Prep HPLC (Method C, 50-100% over 10 min, hold 100% for5 min) to afford Example 532 (12.2 mg, 0.018, 54% yield) as a yellowsolid over the three step sequence. LC-MS: Method H, RT=1.13 min, MS(ESI) m/z: 659.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.08 (br. s., 1H),8.78 (s, 2H), 8.62 (s, 1H), 8.48 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.88(d, J=11.7 Hz, 1H), 7.72 (s, 1H), 5.06 (dd, J=6.4, 2.6 Hz, 1H),4.83-4.74 (m, 2H), 4.74-4.64 (m, 1H), 4.46 (q, J=7.0 Hz, 2H), 2.55 (s,3H), 1.37 (t, J=7.0 Hz, 3H), 1.33 (d, J=6.6 Hz, 6H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −133.47 (s, 1F). ³¹P NMR (162 MHz, DMSO-d₆) δ 24.2 (s, 1P)

Example 533(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(5-hydroxypyridin-3-yl)carbamate

Intermediate 533A: 5-((tert-butyldimethylsilyl)oxy)pyridin-3-amine

To a vial containing 5-aminopyridin-3-ol (75 mg, 0.681 mmol) was addedDCM (6986 μl) and THF (3493 μl) followed by Et₃N (285 μl, 2.043 mmol).TBS-Cl (123 mg, 0.817 mmol) was then added to the solution at roomtemperature. After 1 h of stirring, MeOH (551 μl, 13.62 mmol) was addedto quench the remaining TBS-Cl. The reaction mixture was then dilutedwith EtOAc and washed with brine. The resulting organic phase was driedover MgSO₄, filtered over Celite, concentrated and co-evaporated withtoluene to afford Intermediate 533A (150 mg, 0.669 mmol, 98% yield) as abrown oil. LC-MS: Method H, RT=0.77 min, MS (ESI) m/z: 225.2 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.73 (d, J=2.4 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H),6.49 (t, J=2.3 Hz, 1H), 3.65 (br. s., 2H), 0.98 (s, 9H), 0.21 (s, 6H).

Intermediate 533B:(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-((tert-butyldimethylsilyl)oxy)pyridin-3-yl) carbamate

To a solution Intermediate I-72 (95 mg, 0.230 mmol) in THF (4595 μl) wasadded 15% phosgene in toluene (1620 μl, 2.298 mmol). The resultingslurry was allowed to stir at room temperature overnight. After 16 h,the reaction mixture was concentrated to remove excess phosgene. Theresulting crude chloroformate was retaken in DCM (2290 μl) and slowlyadded to a pre-mixed suspension of Intermediate 533A and pyridine (185μl, 2.290 mmol) in DCM (2290 μl). After 10 min, the reaction mixture wasconcentrated and purified by ISCO (24 g, 0-80% DCM/EtOAc, Product at33%) to afford Intermediate 533B (110 mg, 0.133 mmol, 57.9% yield) as ayellow solid. LC-MS: Method H, RT=1.22 min, MS (ESI) m/z: 664.1 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 8.03 (d,J=2.2 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.82 (d, J=11.2 Hz, 1H), 7.77(dd, J=1.8, 0.9 Hz, 1H), 7.60 (br. s., 1H), 7.53 (d, J=7.7 Hz, 1H), 6.67(br. s., 1H), 5.21-5.12 (m, 1H), 4.60 (qd, J=6.2, 3.3 Hz, 1H), 4.13 (s,3H), 2.65 (s, 3H), 1.47 (d, J=6.4 Hz, 3H), 1.43 (d, J=6.4 Hz, 3H), 0.23(s, 6H), 0.00 (s, 9H).

Example 533

To a solution of Intermediate 533B (25 mg, 0.030 mmol) in THF (1 mL) wasadded acetic acid (0.017 mL, 0.301 mmol) followed by TBAF (1 M in THF)(0.090 mL, 0.090 mmol) (10:35 am). The resulting mixture was stirred atroom temperature for 20 min, before being concentrated and purified byPrep HPLC (Method D, 45-90% over 22 min, hold at 100% for 5 min) toafford Example 533 (9.3 mg, 0.016 mmol, 54% yield). LC-MS: Method H,RT=1.00 min, MS (ESI) m/z: 550.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ9.82 (br. s., 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.10 (br. s., 1H), 7.99(d, J=7.9 Hz, 1H), 7.92 (d, J=11.6 Hz, 1H), 7.77 (s, 2H), 7.45 (br. s.,1H), 5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.77 (dd, J=6.4, 2.7 Hz, 1H), 4.06(s, 3H), 2.60 (s, 3H), 1.39 (dd, J=10.7, 6.4 Hz, 6H).

Example 534(2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl (5-(2-hydroxyethoxy)pyridin-3-yl)carbamate

Intermediate 534A: methyl2-((5-(((((2R,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyridin-3-yl)oxy)acetate

To a solution of Example 533 (25 mg, 0.045 mmol) in DMF (1 mL) was addedcesium carbonate (22.23 mg, 0.068 mmol) followed by methyl bromoacetate(5.03 μl, 0.055 mmol). After 1.5 h of vigorous stirring and roomtemperature, the reaction mixture was diluted with EtOAc and filteredover a short pad of SiO₂ gel. The resulting organic phase wasconcentrated to remove residual DMF, retaken in EtOAc, washed withbrine, dried over MgSO₄, filtered and concentrated to affordIntermediate 534A (22 mg, 0.035 mmol, 78% yield) as a thick yellow oil.LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 622.1 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.59 (d, J=1.8 Hz, 1H), 8.53 (s, 1H), 8.07 (d, J=1.8 Hz,1H), 8.03 (d, J=2.4 Hz, 1H), 7.81 (d, J=11.2 Hz, 1H), 7.75 (s, 1H), 7.70(br. s., 1H), 7.51 (d, J=7.9 Hz, 1H), 6.92 (br. s., 1H), 5.20-5.09 (m,1H), 4.67 (s, 2H), 4.64-4.54 (m, 1H), 4.12 (s, 3H), 3.81 (s, 3H), 2.64(s, 3H), 1.46 (d, J=6.6 Hz, 3H), 1.44-1.41 (m, 3H).

Example 534

A solution of Intermediate 534A (11 mg, 0.018 mmol) in THF (1 mL) wascooled to −78° C. To this mixture was added DIBAL-H (1 M in toluene)(0.088 mL, 0.088 mmol). Following the reagent addition, the reactionmixture was allowed to thaw to room temperature. After 30 min ofvigorous stirring, the reaction mixture was quenched with 1 M HCl,concentrated, and purified by Prep HPLC (Method D, 45-90% over 20 min,hold 100% for 5 min) to afford Example 534 (1.8 mg, 0.002 mmol, 16%yield) as a yellow solid. LC-MS: Method H, RT=0.91 min, MS (ESI) m/z:594.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.87 (br. s., 1H), 8.66 (s,1H), 8.51 (s, 1H), 8.22 (br. s., 1H), 7.98 (d, J=7.9 Hz, 1H), 7.91 (d,J=11.3 Hz, 2H), 7.78 (s, 1H), 7.51 (br. s., 1H), 5.10 (d, J=6.4 Hz, 1H),4.79 (d, J=4.0 Hz, 1H), 4.06 (s, 3H), 3.99 (t, J=4.6 Hz, 2H), 3.72-3.59(m, 2H), 2.60 (s, 3H), 1.38 (dd, J=9.6, 6.6 Hz, 6H).

Example 535(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-((S)-1-hydroxyethyl)pyrimidin-5-yl)carbamate

A solution of Intermediate I-90 (50 mg, 0.085 mmol) in THF (1693 μl) wascooled to −78° C. To this cooled mixture was added DIBAl-H (1 M intoluene) (425 μl, 0.425 mmol), which caused the solution to take on areddish hue. After 1 h, the reaction mixture was quenched cold with 1.7mL of Rochelle's Salt, allowed to thaw to room temperature, and stirredvigorously overnight. After 16 h, the reaction mixture was diluted withEtOAc and extracted. The organic phase was dried over MgSO₄, filteredover Celite and concentrated. The crude residue was purified by ISCO (12g, 0-100% EtOAc/DCM, Pdt at 50%) to afford Example 535 (44 mg, 0.074mmol, 88% yield) as a diastereomeric mixture. This material was furtherpurified by chiral HPLC (Chiracel OD, Semi-prep-80% Heptane/20%EtOH/MeOH(1:1) isocratic eluent with a 16 mL/min flow rate. Diastereomerretention time 60-75 min) to afford homochiral Example 535 (16.4 mg,0.027 mmol, 37% yield). LC-MS: Method H, RT=1.20 min, MS (ESI) m/z:593.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (br. s., 1H), 8.75 (s,2H), 8.64 (s, 1H), 8.50 (d, J=1.8 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.89(d, J=11.7 Hz, 1H), 7.75 (dd, 0.9 Hz, 1H), 5.11-4.98 (m, 2H), 4.77-4.69(m, 1H), 4.68-4.59 (m, 1H), 4.47 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.38(t, J=7.0 Hz, 3H), 1.33 (dd, J=6.5, 2.5 Hz, 6H), 1.28 (d, J=6.4 Hz, 3H).

Example 536(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (2-(((R)-1-hydroxyethyl)pyrimidin-5-yl)carbamate

Example 536 was synthesized concurrently with Example 535 above. Thus,the above diastereomeric mixture was purified by chiral HPLC (ChiracelOD, Semi-prep-80% Heptane/20% EtOH/MeOH(1:1) isocratic eluent with a 16mL/min flow rate. Diastereomer retention time 85-100 min) to affordhomochiral Example 536 (17.2 mg, 0.028 mmol, 37% yield). LC-MS: MethodH, RT=1.20 min, MS (ESI) m/z: 593.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.95 (br. s., 1H), 8.75 (s, 2H), 8.64 (s, 1H), 8.50 (d, J=2.0 Hz, 1H),7.98 (d, J=8.1 Hz, 1H), 7.89 (d, J=11.7 Hz, 1H), 7.75 (s, 1H), 5.10-4.99(m, 2H), 4.74 (dd, J=6.3, 2.8 Hz, 1H), 4.68-4.60 (m, 1H), 4.47 (q, J=7.0Hz, 2H), 2.56 (s, 3H), 1.38 (t, J=7.0 Hz, 3H), 1.33 (dd, J=6.3, 2.5 Hz,6H), 1.28 (d, J=6.6 Hz, 3H).

Example 5372-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl(2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate

Intermediate 537A:2-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl(2-(2-((tert-butyldiphenyl silyl)oxy)ethyl)pyrimidin-5-yl)carbamate

To a solution Intermediate I-66 (15 mg, 0.039 mmol) in THF (1 mL) wasadded 15% phosgene in toluene (0.274 mL, 0.389 mmol). The resultingslurry was allowed to stir overnight. After 16 h the reaction mixturewas concentrated to a crude yellow residue. The resulting chloroformateintermediate was retaken in THF (1 mL) and added dropwise to a pre-mixedsolution of Intermediate I-98 (13.49 mg, 0.036 mmol) and pyridine (0.014mL, 0.179 mmol) in THF (1 mL). After 10 min of stirring at roomtemperature, the reaction mixture was concentrated in vacuo to removeexcess pyridine, and Intermediate 537A was telescoped into thesubsequent deprotection step without further purification. LC-MS: MethodH, RT=1.46 min, MS (ESI) m/z: 789.0 (M+H)⁺.

Example 537

To a crude solution of Intermediate 537A (14 mg, 0.018 mmol) in THF(0.75 mL) and MeOH (0.75 mL) was added (R)-(−)-camphorsulfonic acid(12.37 mg, 0.053 mmol). The reaction vial was sealed and heated to 65°C. After 1.5 h of heating, the reaction mixture was cooled to roomtemperature and quenched with triethylamine (0.025 mL, 0.177 mmol). Theresulting mixture was concentrated, and purified by Prep HPLC (Method D,40-80% over 22 min, hold at 100% for 5 min) to afford Example 537 (5.2mg, 0.009 mmol, 52% yield) as a yellow solid over the three stepsequence. LC-MS: Method H, RT=1.04 min, MS (ESI) m/z: 550.9 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 10.16 (br. s., 1H), 8.79 (s, 2H), 8.72 (s, 1H),8.55 (s, 1H), 8.03-7.94 (m, 2H), 7.82 (s, 1H), 4.57 (br. s., 2H), 4.45(br. s., 2H), 4.08 (s, 3H), 3.82 (q, J=6.4 Hz, 2H), 2.97 (t, J=6.7 Hz,2H), 2.63 (s, 3H).

Example 538(2R,3S)-3-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(2-hydroxyethyl)pyrimidin-5-yl)carbamate

Example 538 was prepared in a manner analogous to Example 536 above.Thus, Intermediate I-81 was reacted with phosgene, followed byIntermediate I-98, followed by CSA to afford Example 538 (66% yield overthe three step sequence) after purification by Prep HPLC (Method D,55-90% over 25 min, hold at 90% for 4 min). LC-MS: Method H, RT=1.18min, MS (ESI) m/z: 612.9, 614.9 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.97(br. s., 1H), 8.76 (br. s., 2H), 8.70 (s, 1H), 8.56 (s, 1H), 8.06 (d,J=7.6 Hz, 1H), 7.83 (s, 1H), 5.14 (dd, J=6.6, 2.6 Hz, 1H), 4.85 (d,J=6.4 Hz, 1H), 4.09 (s, 3H), 3.84-3.74 (m, 2H), 3.34 (br. s., 1H), 2.94(t, J=6.7 Hz, 2H), 2.65 (s, 3H), 1.43 (d, J=6.4 Hz, 3H), 1.40 (d, J=6.4Hz, 3H).

Example 539(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate

Intermediate 539A: methyl5-(((((2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate

To a solution Intermediate I-91 (30 mg, 0.069 mmol) in THF (1386 μl) wasadded 15% phosgene in toluene (489 μl, 0.693 mmol). The resulting slurrywas allowed to stir overnight. After 16 h, the mixture was concentratedto remove the excess phosgene. The resulting chloroformate was retakenin DCM (7.00 mL) and slowly added to a pre-mixed solution ofIntermediate I-107 (39.6 mg, 0.209 mmol) and pyridine (0.084 mL, 1.044mmol) in DCM (1.4 mL). After 30 min, the reaction mixture wasconcentrated and purified by ISCO (12 g, 0-100% EtOAC/DCM) to affordIntermediate 539A (24 mg, 0.029 mmol, 42.3% yield). LC-MS: Method H,RT=1.14 min, MS (ESI) m/z: 612.2, 614.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ 9.04 (s, 2H), 8.75 (d, J=3.1 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H),7.84-7.75 (m, 2H), 7.54 (d, J=7.9 Hz, 1H), 7.38 (d, J=2.9 Hz, 1H),5.23-5.10 (m, 1H), 4.70-4.60 (m, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 1.48(d, J=6.4 Hz, 3H), 1.45 (d, J=6.4 Hz, 4H).

Example 539

Example 539 was prepared in a manner analogous to the primary alcoholsdescribed in the table above. Thus, Intermediate 539A was reacted withDIBAl-H to afford Example 539 (10% yield) following purification by PrepHPLC (Method D, 45-90% over 22 min, hold at 100% for 5 min). LC-MS:Method H, RT=1.09 min, MS (ESI) m/z: 584.2, 586.1 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 10.04 (br. s., 1H), 8.88 (br. s., 1H), 8.83 (br. s.,2H), 8.64 (br. s., 1H), 8.21 (br. s., 1H), 8.06 (d, J=7.6 Hz, 1H),8.01-7.91 (m, 2H), 5.14 (br. s., 1H), 4.82 (br. s., 1H), 4.51 (br. s.,2H), 4.00 (br. s., 3H), 1.41 (br. s., 6H).

Example 540(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate

Intermediate 540A:(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidin-5-yl)carbamate

To a solution of Intermediate I-91 (40 mg, 0.092 mmol) in THF (1848 μl)was added 15% phosgene in toluene (652 μl, 0.924 mmol). The resultingslurry was allowed to stir overnight. After 16 h, the mixture wasconcentrated to remove the excess phosgene. The resulting chloroformatewas retaken in THF (1.0 mL) and added dropwise to a pre-mixed solutionof Intermediate I-104 (19.19 mg, 0.068 mmol) and pyridine (0.036 mL,0.451 mmol) in THF (1 mL). After 10 min, the reaction mixture wasconcentrated to remove excess pyridine and telescoped into the TBSdeprotection without further purification. LC-MS: Method H, RT=1.48 min,MS (ESI) m/z: 742.0, 744.0 (M+H)⁺.

Example 540

To a crude solution of Intermediate 540A (33 mg, 0.044 mmol) in THF(0.75 mL) and MeOH (0.750 mL) was added R(-(−)-camphor sulfonic acid(31.0 mg, 0.133 mmol). The reaction vial was sealed and heated to 65° C.After 30 min of heating, the mixture was cooled to room temperature andtriethylamine (0.062 mL, 0.445 mmol) was added to quench the reaction.The reaction mixture was concentrated and purified by Prep HPLC (MethodD, 55-100% over 20 min, hold at 100% for 7 min) to afford Example 540(17.6, 0.027 mmol, 62% yield) as a yellow solid. LC-MS: Method H,RT=1.17 min, MS (ESI) m/z: 628.0, 629.9 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.80 (br. S., 1H), 8.86 (br. S., 1H), 8.62 (br. S., 3H), 8.19(s, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.97 (d, J=11.3 Hz, 1H), 7.94 (br. S.,1H), 5.10 (d, J=6.4 Hz, 1H), 4.82 (br. S., 1H), 4.12-4.06 (m, 1H),4.03-3.97 (m, 4H), 3.92 (d, J=10.7 Hz, 1H), 1.40 (t, J=6.3 Hz, 6H), 1.12(d, J=6.1 Hz, 3H).

Example 541(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-((S)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate

Example 541 was prepared in a manner analogous Example 540 describedabove. Thus, Intermediate I-91 was reacted with phosgene, followed byIntermediate I-103, followed by CSA to afford Example 541 (72% yieldover the three step sequence) after purification by Prep HPLC (Method D,60-100% over 20 min, hold at 100% for 6 min). LC-MS: Method H, RT=1.17min, MS (ESI) m/z: 628.0, 629.9 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.80(br. s., 1H), 8.84 (d, J=2.1 Hz, 1H), 8.60 (br. s., 3H), 8.17 (s, 1H),8.03 (d, J=7.9 Hz, 1H), 7.95 (d, J=11.3 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H),5.10 (d, J=6.4 Hz, 1H), 4.89 (d, J=4.9 Hz, 1H), 4.82 (d, J=4.0 Hz, 1H),4.12-4.05 (m, 1H), 4.05-4.00 (m, 1H), 3.99 (s, 3H), 3.93 (dt, J=11.4,5.6 Hz, 1H), 1.44-1.34 (m, 6H), 1.11 (d, J=6.4 Hz, 3H).

Preparation of Carbamate Examples

To a solution of the appropriately substituted quinoxaline-benzothiazolealcohol (1.0 equiv) in THF (0.05 M) was added a solution of phosgene(15% by wt. in toluene, 10 equiv). This solution was stirred at roomtemperature overnight before the intermediate chloroformate wasconcentrated in vacuo. This crude chloroformate was retaken in THF (0.05M) and added dropwise to a pre-mixed solution of pyridine (10 equiv) andthe appropriately substituted amino-heterocycle (1.1-3.0 equiv) ineither THF (0.05 M) or DCM (0.05), whichever gave the best reagentsolubility. After 30 min of stirring, the combined mixture wasconcentrated, retaken in DMF, filtered and purified by preparative HPLCto yield the desired example.

If the reactant amino-heterocycle contained a silyl protecting group,the silyl group was removed according to Procedure J before finalpurification. If the reactant amino-heterocycle contained an acetonideprotecting group, the ketal was removed according to Procedure K beforefinal purification.

HPLC LCMS LCMS Prep Ex. [M + H]⁺ RT Method No. Structure R—OH R—NH₂ m/z(Min) D NMR 542

I-69 I-109 598.1 Ortho- gonal HPLC method B Injection 2, 2.136 45- 90%20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.90 (br. s., 1H),8.40-8.75 (m, 3H), 7.70-7.99 (m, 3H), 7.26 (d, J = 8.24 Hz, 1H), 5.32(br. s., 1H), 4.27-4.49 (m, 2H), 4.11 (s, 3H), 3.75 (br. s., 2H),2.81-2.91 (m, 2H), 2.66 (s, 3H), 1.48 (d, J = 6.10 Hz, 3H). 543

I-67 I-109 564.2 Ortho- gonal HPLC method B Injection 2, 1.962 40- 80% 5min, 100% 20 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.96-9.57 (m, 1H), 8.75 (s,1H), 8.62-8.49 (m, 2H), 8.10- 7.94 (m, 2H), 7.84 (s, 1H), 7.81-7.74 (m,1H), 7.19 (d, J = 8.5 Hz, 1H), 5.32-5.15 (m, 1H), 4.67-4.53 (m, 1H),4.41- 4.23 (m, 2H), 4.13-4.05 (m, 3H), 3.69 (t, J = 6.9 Hz, 2H), 2.80(t, J = 7.0 Hz, 2H), 2.66- 2.59 (m, 3H), 1.42 (d, J = 6.6 Hz, 3H). 544

I-67 I-112 564.1 Ortho- gonal HPLC method B Injection 2, 1.961 40- 80%20 min, 100% 6 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.81 (br. s., 1H), 8.63(s, 1H), 8.46 (s, 1H), 8.34 (br. s., 1H), 7.95-7.81 (m, 3H), 7.72 (s,1H), 5.19 (d, J = 3.1 Hz, 1H), 4.40 (br. s., 2H), 4.32-4.11 (m, 2H),2.54 (s, 3H), 2.44 (br. s., 3H), 2.26 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H).545

I-67 I-94 564.15 Ortho- gonal HPLC method B Injection 2, 1.960 50- 100%15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.64 (s,1H), 8.48 (s, 1H), 8.21 (d, J = 5.5 Hz, 1H), 7.98-7.84 (m, 2H), 7.74 (s,1H), 7.29 (s, 1H), 7.23 (d, J = 5.2 Hz, 1H), 5.20 (d, J = 3.1 Hz, 1H),4.33-4.26 (m, 1H), 4.26-4.16 (m, 1H), 4.00 (s, 3H), 3.63 (t, J = 6.9 Hz,2H), 2.71 (t, J = 6.7 Hz, 2H), 2.55 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H).546

I-67 I-385B 550.2 Ortho- gonal HPLC method B Injection 2, 1.995 15- 100%15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.96 (br. s., 1H), 8.70(s, 1H), 8.62-8.45 (m, 2H), 8.06-7.84 (m, 3H), 7.80 (s, 1H), 7.40 (d, J= 8.2 Hz, 1H), 5.25 (d, J = 3.1 Hz, 1H), 4.50-4.46 (m, 2H), 4.39-4.18(m, 2H), 4.06 (s, 3H), 2.60 (s, 3H), 1.50-1.20 (m, 3H). 547

I-72 I-94 578.19. Ortho- gonal HPLC method B Injection 2, 2.058 30- 80%15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.13 (s, 1H), 8.76 (s,1H), 8.60 (s, 1H), 8.31 (d, J = 5.5 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H),8.00 (d, J = 11.3 Hz, 1H), 7.87 (s, 1H), 7.46-7.28 (m, 2H), 5.18 (d, J =4.6 Hz, 1H), 4.84 (br. s., 1H), 4.13 (s, 3H), 3.75 (t, J = 6.7 Hz, 2H),3.57-3.43 (m, 1H), 2.89-2.76 (m, 2H), 2.67 (s, 3H), 1.46 (t, J = 6.4 Hz,6H). 549

I-72 I-111 608.20 Ortho- gonal HPLC method B Injection 2, 2.178 30- 80%22 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.08 (s, 1H), 8.72 (s,1H), 8.56 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.99-7.89 (m, 2H), 7.82 (s,1H), 7.01 (d, J = 5.4 Hz, 1H), 6.85 (s, 1H), 5.19-5.01 (m, 2H),4.89-4.74 (m, J = 3.7 Hz, 1H), 4.08 (s, 3H), 3.56-3.34 (m, 2H), 2.63 (s,3H), 1.40 (t, J = 6.1 Hz, 6H), 1.17 (d, J = 6.1 Hz, 3H). 550

I-72 I-111 608.20 Ortho- gonal HPLC method B Injection 2, 2.167 30- 80%22 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.70 (s,1H), 8.54 (s, 1H), 8.05-7.89 (m, 3H), 7.80 (s, 1H), 7.02 (d, J = 4.7 Hz,1H), 6.91 (s, 1H), 5.12 (d, J = 4.0 Hz, 1H), 4.79 (br. s., 1H),4.04-3.85 (m, 3H), 2.62 (s, 3H), 1.40 (t, J = 5.6 Hz, 6H), 1.09 (d, J =6.4 Hz, 3H). 552

I-67 I-110 580.1 Ortho- gonal HPLC method B Injection 2, 2.003 30- 100%20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.17 (s, 1H), 8.70 (s,1H), 8.59-8.49 (m, J = 1.5 Hz, 1H), 8.03-7.89 (m, 3H), 7.80 (s, 1H),7.06 (dd, J = 5.6, 1.7 Hz, 1H), 6.93 (s, 1H), 5.35-5.21 (m, 1H),4.43-4.24 (m, 2H), 4.24-4.16 (m, J = 5.0, 5.0 Hz, 2H), 4.07 (s, 3H),3.68 (q, J = 5.5 Hz, 2H), 3.43 (br. s., 2H), 2.62 (s, 3H), 1.43 (d, J =6.4 Hz, 3H). 553

I-67 I-106 595.15. Ortho- gonal HPLC method B Injection 2, 2.265 45-100% 20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.85 (br. s., 1H),8.65 (s, 1H), 8.60 (br. s., 2H), 8.50 (s, 1H), 7.97-7.87 (m, 2H), 7.77(s, 1H), 5.29-5.19 (m, 1H), 5.10-4.97 (m, 1H), 4.42-4.20 (m, 2H), 4.06(s, 3H), 3.60-3.55 (m, 2H), 2.60 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H). 554

I-72 I-106 609.19 Ortho- gonal HPLC method B Injection 2, 2.348 50- 100%20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.89-9.70 (m, 1H), 8.68(s, 1H), 8.59 (br. s., 2H), 8.53 (s, H), 8.01 (d, J = 8.2 Hz, 1H), 7.93(d, J = 11.6 Hz, 1H), 7.80 (s, 1H), 5.20-4.53 (m, 3H), 4.07 (s, 3H),3.60-3.47 (m, 1H), 2.61 (s, 3H), 1.44-1.31 (m, 6H), 1.21 (d, J = 6.1 Hz,3H). 555

I-67 I-97 581.1. LCMS Method H, 1.11 50- 100% 10 min, 100% 5 min ¹H NMR(400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.68-8.54 (m, 3H), 8.12-7.94 (m, 2H),7.85 (s, 1H), 5.34-5.14 (m, 1H), 4.99- 4.75 (m, 1H), 4.44-4.32 (m, 1H),4.32-4.17 (m, J = 5.0, 5.0 Hz, 3H), 4.09 (s, 3H), 3.75-3.61 (m, 2H),2.64 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H). 556

I-72 I-97 595.2 LCMS Method H, 1.16 50- 100% 10 min, 100% 8 min ¹H NMR(400 MHz, DMSO-d₆) δ 9.72 (br. s., 1H), 8.67 (s, 1H), 8.53 (br. s., 2H),8.51 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 11.7Hz, 1H), 7.77 (d, J = 0.7 Hz, 1H), 5.02 (qd, J = 6.5, 2.8 Hz, 1H),4.80-4.68 (m, 2H), 4.16 (t, J = 5.1 Hz, 2H), 4.02 (s, 3H), 3.60 (q, J =5.4 Hz, 2H), 2.56 (s, 3H), 1.31 (m, 6H). 557

I-67 I-92 592.36 Ortho- gonal HPLC method B Injection 2, 2.052 40- 100%10 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.86 (br. s., 1H), 8.67(s, 1H), 8.57-8.45 (m, 2H), 8.05-7.89 (m, 2H), 7.84-7.71 (m, 2H), 7.23(d, J = 8.2 Hz, 1H), 5.30- 5.16 (m, J = 6.3, 3.2 Hz, 1H), 4.40-4.19 (m,2H), 4.06 (s, 3H), 2.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.06 (s, 6H).558

I-67 I-105 595.20 Ortho- gonal HPLC method B Injection 2, 2.270 45- 100%20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.67 (br.s., 2H), 8.58 (s, 1H), 8.05-7.93 (m, 2H), 7.85 (s, 1H), 5.40-5.25 (m,1H), 5.15-4.91 (m, 1H), 4.46-4.27 (m, 2H), 3.57 (s, 3H), 2.62 (s, 2H),1.48 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.1 Hz, 3H). 559

I-72 I-92 606.35 Ortho- gonal HPLC method B Injection 2, 2.138 40- 100%12 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.83-9.57 (m, 1H), 8.62(s, 1H), 8.52-8.42 (m, 2H), 7.96 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 11.6Hz, 1H), 7.75 (s, 2H), 7.19 (d, J = 8.5 Hz, 1H), 5.09 (dd, J = 6.4, 2.7Hz, 1H), 4.77 (dd, J = 6.3, 2.6 Hz, 1H), 4.05 (s, 3H), 1.38 (dd, J =11.1, 6.3 Hz, 7H), 1.03 (s, 6H). 560

I-72 I-105 609.20 Ortho- gonal HPLC method B Injection 2, 2.362 35- 75%20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.73 (br. s., 1H),8.76-8.34 (m, 4H), 8.02-7.85 (m, 3H), 7.75 (s, 1H), 5.16-4.91 (m, 2H),4.79 (br. s., 1H), 4.09-3.97 (m, 4H), 3.72-3.65 (m, 3H), 2.58 (s, 3H),1.43-1.33 (m, 6H), 1.18 (d, J = 6.4 Hz, 3H). 561

I-72 1-95 606.22 Ortho- gonal HPLC method B Injection 2, 2.253 15- 100%19 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.57 (s,1H), 8.04-7.86 (m, 3H), 7.83 (s, 1H), 6.44-6.31 (m, 2H), 6.13 (br. s.,1H), 4.95 (dd, J = 6.4, 3.1 Hz, 1H), 4.73 (dd, J = 6.1, 3.1 Hz, 1H),4.09 (s, 3H), 3.10-3.02 (m, 1H), 2.99-2.92 (m, 1H), 2.63 (s, 3H), 1.41(s, 3H), 1.40 (s, 3H), 1.37-1.29 (m, J = 5.8, 5.8 Hz, 7H). 562

I-72 I-96 622.21 Ortho- gonal HPLC method B Injection 2, 2.199 50- 100%20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.13 (s, 1H), 8.75 (s,1H), 8.60 (d, J = 1.5 Hz, 1H), 8.16- 7.80 (m, 4H), 7.12-6.86 (m, 2H),5.30-5.11 (m, J = 6.4, 2.7 Hz, 1H), 4.97-4.81 (m, J = 6.4, 2.7 Hz, 1H),4.13 (s, 3H), 4.02 (s, 2H), 2.67 (s, 3H), 1.45 (t, J = 6.1 Hz, 6H), 1.20(s, 6H). 563

I-72 I-108 636.26 Ortho- gonal HPLC method B Injection 2, 2.190 50- 100%20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.62 (s,1H), 8.47 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.89-7.81 (m, 2H), 7.73 (s,1H), 6.92 (d, J = 4.3 Hz, 1H), 6.80 (s, 1H), 5.09-4.99 (m, J = 6.7, 2.7Hz, 1H), 4.78- 4.67 (m, J = 6.3, 2.6 Hz, 1H), 4.21 (t, J = 7.2 Hz, 2H),4.00 (s, 3H), 2.55 (s, 3H), 1.71 (t, J = 7.3 Hz, 2H), 1.32 (t, J = 6.6Hz, 6H), 1.06 (s, 6H). 564

I-67 I-98 565.15 Ortho- gonal HPLC method B Injection 2, 2.111 45- 85%25 min, 100% 6 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.80-8.62 (m, 3H), 8.50(s, 1H), 7.99-7.88 (m, 2H), 7.78 (s, 1H), 5.27 (d, J = 2.7 Hz, 1H),4.40-4.32 (m, J = 8.2 Hz, 1H), 4.31-4.20 ( m, J = 10.8, 6.3 Hz, 1H),4.06 (s, 3H), 3.81 (q, J = 6.4 Hz, 2H), 2.95 (t, J = 6.7 Hz, 2H), 2.60(s, 3H), 1.42 (d, J = 6.4 Hz, 3H). 565

I-72 I-98 579.18 Ortho- gonal HPLC method B Injection 2 Injection 2,2.298 45- 90% 25 min, 100% 6 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.78-8.67(m, 3H), 8.55 (s, 1H), 8.04-7.89 (m, 2H), 7.83 (s, 1H), 5.19-5.05 (m,1H), 4.85- 4.77 (m, 1H), 3.79 (d, J = 5.8 Hz, 2H), 2.93 (t, J = 6.7 Hz,2H), 1.39 (t, J = 6.9 Hz, 6H). 566

I-80 I-98 593.24 Ortho- gonal HPLC method B Injection 2, 2.359 50- 100%20 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br. s., 1H), 8.75(br. s., 2H), 8.63 (s, 1H), 8.51 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.92(d, J = 11.3 Hz, 1H), 7.76 (s, 1H), 5.12 (dd, J = 6.6, 2.6 Hz, 1H), 4.79(d, J = 4.0 Hz, 1H), 4.66 (t, J = 5.5 Hz, 1H), 4.51 (q, J = 7.0 Hz, 2H),3.87-3.62 (m, 2H), 2.94 (t, J = 6.7 Hz, 2H), 2.56 (s, 3H), 1.54-1.28 (m,9H). 567

I-67 I-108 622.2 Ortho- gonal HPLC method B Injection 2, 2.087 50- 100%20 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.13 (s, 1H), 8.70 (s,1H), 8.54 (s, 1H), 8.09-7.91 (m, 3H), 7.81 (s, 1H), 7.01 (d, J = 5.8 Hz,1H), 6.90 (s, 1H), 5.26 (br. s., 1H), 4.45-4.14 (m, 4H), 4.08 (s, 3H),2.62 (s, 3H), 1.79 (t, J = 7.2 Hz, 2H), 1.42 (d, J = 6.4 Hz, 3H), 1.14(s, 6H). 568

I-80 I-97 609.19 Ortho- gonal HPLC method B Injection 2, 2.408 30- 100%15 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.57 (s,3H), 8.06-7.92 (m, 2H), 7.82 (s, 1H), 5.14-5.03 (m, 1H), 4.94-4.89 (m,1H), 4.85-4.75 (m, 1H), 4.55 (d, J = 7.0 Hz, 2H), 4.23 (br. s., 2H),3.74-3.63 (m, J = 4.9 Hz, 2H), 2.63 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H),1.42-1.31 (m, 6H). 569

I-67 I-100 623.15 Ortho- gonal HPLC method B Injection 2, 2.345 45- 100%21 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.88 (br. s., 1H),8.71-8.56 (m, 3H), 8.50 (s, 1H), 8.02-7.86 (m, 2H), 7.76 (s, 1H), 5.24(br. s., 1H), 4.41-4.18 (m, 4H), 3.97 (s, 3H), 2.59 (s, 3H), 1.81 (br.s., 2H), 1.41 (d, J = 6.1 Hz, 3H), 1.14 (br. s., 6H). 570

I-72 I-100 637.2 Ortho- gonal HPLC method B Injection 2, 2.436 50- 100%6 min, 100% 22 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.77 (br. s., 1H),8.70-8.42 (m, 4H), 8.09-7.86 (m, 2H), 7.77 (s, 1H), 5.16-5.03 (m, 1H),4.91-4.72 (m, J = 6.4 Hz, 1H), 4.28 (t, J = 6.6 Hz, 2H), 4.05 (s, 3H),2.59 (s, 3H), 1.79 (t, J = 7.1 Hz, 2H), 1.45-1.31 (m, J = 6.7 Hz, 6H),1.19-1.01 (m, 6H). 571

I-72 I-93 594.15 Ortho- gonal HPLC method B Injection 2, 2.303 35- 100%15 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.57 (br. s., 1H), 8.65(s, 1H), 8.50 (s, 1H), 8.16 (br. s., 1H), 8.01-7.86 (m, 2H), 7.77 (s,2H), 6.75 (d, J = 8.2 Hz, 1H), 5.07 (d, J = 6.1 Hz, 1H), 4.77 (d, J =6.1 Hz, 1H), 4.17 (t, J = 4.9 Hz, 2H), 4.06 (s, 3H), 3.67 (d, J = 4.9Hz, 1H), 3.59-3.55 (m, 2H), 2.60 (s, 3H), 1.38 (dd, J = 12.1, 6.3 Hz,6H). 572

I-67 I-93 580.17 Ortho- gonal HPLC method B Injection 2, 2.215 35- 100%10 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.80-9.39 (m, 1H), 8.66(s, 1H), 8.51 (s, 1H), 8.19 (br. s., 1H), 7.97-7.87 (m, 2H), 7.78 (br.s., 2H), 6.77 (d, J = 8.5 Hz, 1H), 5.23 (br. s., 1H), 4.36-4.23 (m, 2H),4.19 (d, J = 4.9 Hz, 2H), 4.06 (s, 3H), 3.68 (d, J = 4.9 Hz, 1H), 3.59(br. s., 1H), 2.60 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H). 573

I-72 I-99 644.18 Ortho- gonal HPLC method B Injection 2, 2.541 45- 100%15 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.65 (br. s., 1H), 8.67(s, 1H), 8.52 (s, 1H), 8.20 (br. s., 1H), 8.02-7.88 (m, 2H), 7.79 (br.s., 2H), 6.86 d, J = 8.2 Hz, 1H), 5.08 (d, J = 4.0 Hz, 1H), 4.78 (d, J =4.0 Hz, 1H), 4.51 (t, J = 13.4 Hz, 2H), 4.06 (s, 3H), 3.78-3.65 (m, 2H),2.61 (s, 3H), 1.38 (dd, J = 11.0, 6.4 Hz, 6H). 574

I-67 I-99 630.16 Ortho- gonal HPLC method B Injection 2, 2.460 35- 100%15 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.85-9.51 (m, 1H), 8.61(s, 1H), 8.46 (s, 1H), 8.20 (br. s., 1H), 7.93-7.68 (m, 4H), 6.86 (d, J= 8.9 Hz, 1H), 5.22 (br. s., 1H), 4.51 (t, J = 13.4 Hz, 2H), 4.37-4.18(m, 2H), 4.04 (s, 3H), 3.75-3.73 (m, 2H), 2.56 (s, 3H), 1.39 (d, J = 6.4Hz, 3H). 575

I-72 I-101 623.2 Ortho- gonal HPLC method B Injection 2, 2.418 40- 80%30 min, 100% 6 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.72 (br. s., 1H), 8.61(s, 1H), 8.53 (br. s., 2H), 8.46 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.86(d, J = 11.3 Hz, 1H), 7.73 (s, 1H), 5.02 (d, J = 6.4 Hz, 1H), 4.73 (d, J= 4.0 Hz, 1H), 4.63 (s, 1H), 4.00 (s, 3H), 3.95-3.89 (m, 2H), 2.54 (s,3H), 1.38- 1.26 (m, 6H), 1.10 (s, 6H). 576

I-67 I-101 609.19 Ortho- gonal HPLC method B Injection 2, 2.340 50- 83%20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.62 (br.s., 2H), 8.52 (s, 1H), 8.00-7.90 (m, 2H), 7.79 (s, 1H), 5.35-5.03 (m,1H), 4.44-4.22 (m, 2H), 4.07 (s, 3H), 2.61 (s, 3H), 1.42 (d, J = 6.4 Hz,3H), 1.18 (s, 6H). 577

I-72 I-102 607.21 Ortho- gonal HPLC method B Injection 2, 2.366 40- 80%25 min, 100% 6 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.14-9.80 (m, 1H),8.84-8.76 (m, 2H), 8.75-8.71 (m, 1H), 8.61-8.55 (m, 1H), 8.08-8.03 (m,1H), 7.99-7.93 (m, 1H), 7.87-7.83 (m, 1H), 5.19-5.03 (m, 1H), 4.91-4.73(m, 1H), 4.13-4.06 (m, 3H), 2.66-2.59 (m, 3H), 1.45-1.32 (m, 6H),1.11-1.04 (m, 6H). 578

I-72 I-103 609.19 Ortho- gonal HPLC method B Injection 2, 2.333 35- 100%20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.85-9.67 (m, 1H), 8.70(d, J = 2.1 Hz, 1H), 8.62-8.51 (m, 3H), 8.06-7.90 (m, 2H), 7.81 (s, 1H),5.16-5.04 (m, J = 6.7 Hz, 1H), 4.90 (br. s., 1H), 4.84-4.73 (m, J = 6.1,2.4 Hz, 1H), 4.07 (s, 4H), 4.04-3.83 (m, 2H), 3.44-3.34 (m, 3H), 2.62(s, 3H), 1.38 (t, J = 6.1 Hz, 6H), 1.10 (d, J = 6.4 Hz, 3H). 579

I-91 I-98 598.13 Ortho- gonal HPLC method B Injection 2, 2.232 45- 90%20 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.11-9.73 (m, 1H), 8.88(br. s., 1H), 8.76 (br. s., 2H), 8.64 (br. s., 1H), 8.20 (br. s., 1H),8.06 (d, J = 7.3 Hz, 1H), 8.01- 7.90 (m, 2H), 5.20-5.04 (m, 1H),4.87-4.73 (m, 1H), 4.00 (br. s., 3H), 3.83-3.65 (m, 2H), 2.97-2.84 (m,2H), 1.47-1.35 (m, 6H). 580

I-80 I-103 623.21 Ortho- gonal HPLC method B Injection 2, 2.466 50- 100%10 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.79 (br. s., 1H),8.76-8.32 (m, 4H), 8.05-7.88 (m, 2H), 7.78 (s, 1H), 5.18-5.03 (m, 1H),4.87-4.73 (m, 1H), 4.52 (q, J = 7.0 Hz, 2H), 4.14-3.76 (m, 3H), 2.61 (s,3H), 1.52-1.33 (m, 10H), 1.11 (d, J = 6.1 Hz, 3H). 581

I-72 I-104 609.1 Ortho- gonal HPLC method B Injection 2, 2.35 50- 100%22 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.79 (br. s., 1H),8.76-8.45 (m, 4H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.3 Hz, 1H),7.82 (s, 1H), 5.17-5.06 (m, J = 4.0 Hz, 1H), 4.86-4.74 (m, J = 3.4 Hz,1H), 4.17-4.05 (m, 4H), 4.04-3.86 (m, 2H), 2.63 (s, 3H), 1.45-1.35 (m,6H), 1.12 (d, J = 6.1 Hz, 3H). 582

I-80 I-104 623.0 Ortho- gonal HPLC method B Injection 2, 2.51 45- 90% 22min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (br. s., 1H), 8.74-8.43(m, 4H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.3 Hz, 1H), 7.79 (s,1H), 5.17-5.05 (m, J = 6.1 Hz, 1H), 4.88-4.73 (m, 1H), 4.54 (q, J = 6.9Hz, 2H), 4.18- 3.86 (m, 3H), 2.62 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H),1.40-1.36 (m, J = 6.7 Hz, 6H), 1.12 (d, J = 6.1 Hz, 3H). 583

I-80 I-114 639.2 Ortho- gonal HPLC method B Injection 2, 2.402 45- 90%22 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.93-9.60 (m, 1H), 8.68(s, 1H), 8.62 (br. s., 2H), 8.55 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.95(d, J = 11.3 Hz, 1H), 7.79 (s, 1H), 5.10 (dd, J = 6.6, 2.6 Hz, 1H), 4.80(dd, J = 6.4, 2.7 Hz, 1H), 4.66 (s, 1H), 4.53 (q, J = 7.0 Hz, 2H), 4.26(dd, J = 11.0, 4.3 Hz, 1H), 4.13 (dd, J = 10.8, 6.6 Hz, 1H), 3.79 (d, J= 4.9 Hz, 1H), 3.43 (t, J = 5.6 Hz, 1H), 3.39-3.28 (m, 1H), 2.62 (s,3H), 1.45 (t, J = 7.0 Hz, 3H), 1.42-1.36 (m, 6H). 584

612 I-98 579.2 Ortho- gonal HPLC method B Injection 2, 2.24 45- 90% 22min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.03 (br. s., 1H), 8.79(br. s., 2H), 8.73 (s, 1H), 8.57 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.95(d, J = 11.6 Hz, 1H), 7.70 (dd, J = 6.9, 2.3 Hz, 2H), 5.19-5.05 (m, 1H),4.79-4.68 (m, 1H), 4.61 (t, J = 5.5 Hz, 1H), 4.09 (s, 3H), 3.81 (q, J =6.2 Hz, 2H), 2.96 (t, J = 6.7 Hz, 2H), 2.63 (s, 3H), 1.45-1.45 (m, 1H),1.39 (dd, J = 11.9, 6.4 Hz, 6H). 585

I-72 I-113 625.3 Ortho- gonal HPLC method B Injection 2, 2.25 45- 90% 18min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.82 (br. s., 1H), 8.71 (s,1H), 8.62 (br. s., 2H), 8.56 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d,J = 11.6 Hz, 1H), 7.82 (s, 1H), 5.11 (dd, J = 6.4, 2.7 Hz, 1H), 4.81(dd, J = 6.1, 2.7 Hz, 1H), 4.29-4.23 (m, 1H), 4.14 (ddd, J = 10.5, 6.6,3.7 Hz, 1H), 4.08 (s, 3H), 3.84-3.71 (m, 1H), 3.46-3.40 (m, 1H),3.52-3.13 (m, 2H), 2.63 (s, 3H), 1.46-1.21 (m, 6H). 586

I-69 I-98 600.1 Ortho- gonal HPLC method B Injection 2, 2.24 50- 100% 20min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.07 (br. s., 1H), 8.78(br. s., 2H), 8.67 (s, 1H), 8.52 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.79(s, 1H), 5.36-5.17 (m, J = 2.7 Hz, 1H), 4.44-4.36 (m, 1H), 4.33-4.27 (m,J = 10.8, 6.0 Hz, 1H), 4.08 (s, 3H), 3.87-3.74 (m, 2H), 2.96 (t, J = 6.9Hz, 2H), 2.63 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H). 587

I-72 I-114 625.0 Ortho- gonal HPLC method B Injection 2, 2.17 45- 90% 18min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.81 (br. s., 1H), 8.71 (s,1H), 8.62 (br. s., 2H), 8.55 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.95 (d,J = 11.3 Hz, 1H), 7.81 (s, 1H), 5.10 (dd, J = 6.4, 2.4 Hz, 1H), 4.96 (d,J = 5.2 Hz, 1H), 4.85-4.74 (m, 1H), 4.68 (t, J = 5.5 Hz, 1H), 4.26 (dd,J = 11.0, 4.0 Hz, 1H), 4.13 (dd, J = 10.8, 6.6 Hz, 1H), 3.84-3.74 (m,1H), 3.68-3.54 (m, 1H), 3.46-3.31 (m, 1H), 2.63 (s, 3H), 1.46-1.17 (m,6H). 588

I-80 I-113 639.1 Ortho- gonal HPLC method B Injection 2, 2.337 55- 90%25 min, 100% 4 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.82 (br. s., 1H), 8.70(s, 1H), 8.62 (br. s., 2H), 8.57 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.96(d, J = 11.6 Hz, 1H), 7.81 (s, 1H), 5.10 (d, J = 6.7 Hz, 1H), 4.95 (d, J= 5.2 Hz, 1H), 4.80 (br. s., 1H), 4.66 (t, J = 5.6 Hz, 1H), 4.54 (q, J =7.0 Hz, 2H), 4.32-4.23 (m, 1H), 4.19-4.10 (m, 1H), 3.83-3.68 (m, 1H),3.43 (t, J = 5.6 Hz, 1H), 3.39- 3.31 (m, 1H), 2.63 (s, 3H), 1.46 (t, J =7.0 Hz, 3H), 1.42-1.36 (m, 6H). 589

I-69 — 569.05 Ortho- gonal HPLC method B Injection 2, 2.218 45- 85% 22min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (br. s., 2H), 8.66 (s,1H), 8.51 (s, 1H), 7.95 (d, J = 7.32 Hz, 1H), 7.78 (s, 1H), 5.25 (br.s., 1H), 4.35-4.46 (m, 1H), 4.22-4.32 (m, 1H), 4.06 (s, 3H), 2.62 (s,3H), 2.52 (s, 3H), 1.42 (d, J = 6.41 Hz, 3H). 590

I-69 — 569.05 Ortho- gonal HPLC method B Injection 2, 2.229 40- 100% 20min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (br. s., 1H), 8.69 (s,1H), 8.54 (s, 1H), 8.20 (d, J = 4.27 Hz, 1H), 7.97 (d, J = 7.32 Hz, 1H),7.81 (s, 1H), 7.71 (d, J = 7.93 Hz, 1H), 6.98-7.25 (m, 1H), 5.24 (br.s., 1H), 4.36 (br. s., 1H), 4.27 (br. s., 1H), 4.06 (s, 3H), 2.63 (s,3H), 2.37 (s, 3H), 1.39 (d, J = 6.41 Hz, 3H. 591

I-69 — 555.10 Ortho- gonal HPLC method B Injection 2, 2.452 30- 90% 21min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.05-10.37 (m, 1H), 8.88(s, 2H), 8.84 (s, 1H), 8.72 (s, 1H), 8.56 (d, J = 1.38 Hz, 1H), 8.01 (d,J = 7.70 Hz, 1H), 7.83 (s, 1H), 5.29 (dd, J = 3.03, 6.33 Hz, 1H), 4.41(dd, J = 3.03, 10.73 Hz, 1H), 4.31 (dd, J = 5.91, 10.87 Hz, 1H),4.07-4.11 (m, 3H), 2.64 (s, 4H), 1.44 (d, J = 6.60 Hz, 4H). 592

I-67 — 534.2 Ortho- gonal HPLC method B Injection 2, 2.063 40- 80% 22min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.84 (br. s., 1H), 8.70 (s,1H), 8.55-8.42 (m, 2H), 8.01-7.91 (m, 2H), 7.82-7.67 (m, 2H), 7.16 (d, J= 8.2 Hz, 1H), 5.36- 5.02 (m, 1H), 4.41-4.17 (m, 2H), 4.06 (s, 3H), 2.60(s, 3H), 2.40-2.23 (m, 3H), 1.40 (d, J = 6.4 Hz, 3H). 593

I-80 I-117 634.9 Ortho- gonal HPLC method B Injection 2, 2.63 60- 100%15 min, 100% 10 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.92 (br. s., 1H), 8.70(br. s., 2H), 8.61 (s, 1H), 8.49 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.90(d, J = 11.6 Hz, 1H), 7.75 (s, 1H), 5.18-5.02 (m, J = 6.6, 2.6 Hz, 1H),4.87-4.71 (m, J = 4.0 Hz, 1H), 4.50 (q, J = 7.0 Hz, 2H), 3.54 (s, 2H),3.03 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H), 2.56 (s, 3H), 1.53-1.12 (m, 9H). 594

612 — 533.9 Ortho- gonal HPLC method B Injection 2, 2.15 45- 90% 22 min,100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.03 (br. s., 1H), 8.75 (s, 1H),8.69 (br. s., 1H), 8.59 (s, 1H), 8.26 (d, J = 4.0 Hz, 1H), 8.07 (d, J =8.2 Hz, 1H), 7.97 (d, J = 11.6 Hz, 2H), 7.84 (s, 1H), 7.44-7.33 (m, 1H),5.18- 4.96 (m, 1H), 4.79-4.64 (m, 1H), 4.10 (s, 3H), 2.56 (s, 3H), 1.39(dd, J = 12.8, 6.4 Hz, 6H). 595

612 — 549.0 Ortho- gonal HPLC method B Injection 2, 2.40 50- 100% 20min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.02 (br. s., 1H),8.90-8.68 (m, 3H), 8.56 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.95 (d, J =11.6 Hz, 1H), 7.82 (s, 1H), 5.27-4.96 (m, 1H), 4.81-4.55 (m, 1H), 4.09(s, 3H), 2.63 (s, 3H), 2.56 (s, 3H), 1.39 (dd, J = 11.9, 6.4 Hz, 6H).596

I-69 I-385A 584.1 Ortho- gonal HPLC method B Injection 2, 2.13 35- 68%25 min 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.88 (br. s., 1H),8.34-8.65 (m, 3H), 7.82-7.98 (m, 2H), 7.73 (s, 1H), 7.37 (d, J = 8.54Hz, 1H), 5.16-5.33 (m, 1H), 4.47 (br. s., 2H), 4.20-4.38 (m, 2H), 4.04(s, 3H), 2.59 (s, 3H), 1.41 (d, J = 6.71 Hz, 3H). 597

I-67 I-115 564.2 Ortho- gonal HPLC method B Injection 2, 2.25 25- 100%20 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (br. s., 1H), 8.72(s, 1H), 8.56 (s, 1H), 8.37 (br. s., 1H), 7.96 (d, J = 11.0 Hz, 2H),7.82 (s, 1H), 5.29-5.07 (m, 1H), 4.32 (br. s., 2H), 4.07 (s, 3H), 3.05(br. s., 6H), 2.62 (s, 3H), 1.38 (d, J = 5.8 Hz, 3H). 598

I-72 I-115 578.2 Ortho- gonal HPLC method B Injection 2, 2.308 40- 80%15 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (br. s., 1H), 8.67(s, 1H), 8.52 (s, 1H), 8.33 (br. s., 2H), 8.07-7.87 (m, 2H), 7.78 (s,1H), 5.03 (d, J = 4.3 Hz, 1H), 4.76 (br. s., 1H), 4.05 (s, 3H), 3.02 (s,6H), 2.59 (s, 3H), 1.43-1.27 (m, 6H). 599

I-72 — 577.20 Ortho- gonal HPLC method B Injection 2, 2.762 70- 100% 12min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.32 (br. s., 1H), 8.69 (s,1H), 8.53 (s, 1H), 8.11 (br. s., 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.93 (d,J = 11.6 Hz, 1H), 7.79 (s, 1H), 7.57 (br. s., 1H), 6.58 (d, J = 8.5 Hz,1H), 5.04 (d, J = 4.3 Hz, 1H), 4.75 (br. s., 1H), 4.06 (s, 3H), 2.93 (s,6H), 2.60 (s, 3H), 1.36 (dd, J = 13.4, 5.8 Hz, 6H). 600

I-72 — 619.15 Ortho- gonal HPLC method B Injection 2, 2.41 50- 100% 10min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.78 (br. s., 1H), 8.68 (s,1H), 8.53 (s, 1H), 8.37 (br. s., 1H), 8.06-7.83 (m, 4H), 7.79 (s, 1H),5.08 (dd, J = 6.6, 2.6 Hz, 1H), 4.80 (dd, J = 6.3, 2.6 Hz, 1H),4.51-4.30 (m, 2H), 4.12- 3.97 (m, 5H), 2.60 (s, 3H), 1.38 (t, J = 6.9Hz, 6H). 601

I-72 — 591.20 Ortho- gonal HPLC method B Injection 2, 2.104 50- 100% 12min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.75 (br. s.,1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.35 (br. s., 1H), 8.09-7.89 (m, 2H),7.79 (s, 1H), 5.08 (dd, J = 6.4, 2.4 Hz, 1H), 4.79 (dd, J = 6.1, 2.7 Hz,1H), 4.06 (s, 3H), 2.60 (s, 3H), 2.03 (s, 3H), 1.38 (t, J = 6.6 Hz, 6H).602

I-72 — 549.20 Ortho- gonal HPLC method B Injection 2, 2.034 45- 90% 25min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (br. s., 1H), 8.70 (s,1H), 8.54 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 11.3 Hz, 2H),7.80 (s, 1H), 7.43 (br. s., 1H), 6.40 (d, J = 8.5 Hz, 1H), 5.03 (d, J =4.0 Hz, 1H), 4.73 (br. s., 1H), 4.06 (s, 3H), 2.61 (s, 3H), 1.44-1.30(m, 6H). 603

I-72 — 619.21 Ortho- gonal HPLC method B Injection 2, 2.267 30- 100% 15min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.51-9.30 (m, 1H), 8.77-8.72(m, 1H), 8.63-8.52 (m, 1H), 8.25-8.13 (m, 1H), 8.07-8.01 (m, 1H),8.00-7.93 (m, 1H), 7.88-7.82 (m, 1H), 7.73-7.58 (m, 1H), 6.90-6.70 (m,1H), 5.13-4.99 (m, 1H), 4.86-4.59 (m, 1H), 4.09 (s, 3H), 3.75-3.61 (m,8H), 2.64 (s, 3H), 1.42-1.31 (m, 6H). 604

I-72 — 706.05 Ortho- gonal HPLC method B Injection 2, 2.525 30- 70% 20min, 100% 5 min ¹H NMR (400MHz, DMSO-d₆) δ 11.06 (br. s., 1H),10.12-9.78 (m, 1H), 8.79 (br. s., 2H), 8.72 (s, 1H), 8.58 (d, J = 1.8Hz, 1H), 8.19 (dd, J = 7.3, 2.2 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H),8.03-7.92 (m, 2H), 7.87-7.76 (m, 1H), 7.57 (t, J = 9.0 Hz, 1H), 5.14(dd, J = 6.6, 2.6 Hz, 1H), 4.86 (dd, J = 6.4, 2.6 Hz, 1H), 4.15-4.02 (m,3H), 2.64 (s, 3H), 1.51-1.37 (m, 6H). 605

I-72 — 602.55 Ortho- gonal HPLC method B Injection 2, 2.196 40- 80% 20min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (br. s., 1H), 8.68 (s,1H), 8.53 (s, 1H), 8.11-7.88 (m, 4H), 7.78 (s, 1H), 7.53 (br. s., 1H),6.35 (br. s., 1H), 5.03 (d, J = 4.3 Hz, 1H), 4.75 (br. s., 1H),4.11-4.02 (m, 3H), 3.27 (br. s., 2H), 2.60 (s, 3H), 1.88 (br. s., 4H),1.36 (dd, J = 14.5, 5.3 Hz, 8H). 606

I-72 — 622.0 Ortho- gonal HPLC method B Injection 2, 2.219 30- 70% 20min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.33 (br. s., 1H), 8.67 (s,1H), 8.52 (s, 1H), 8.27 (br. s., 2H), 8.03-7.88 (m, 2H), 7.78 (s, 1H),5.03 (d, J = 6.4 Hz, 1H), 4.75 (br. s., 1H), 4.05 (s, 3H), 3.22 (d, J =5.8 Hz, 2H), 2.60 (s, 3H), 1.47-1.24 (m, 6H), 1.06 (s, 6H). 607

I-72 I-116 642.16 Ortho- gonal HPLC method B Injection 2, 2.517 30- 70%20 min, 100% 5 min ¹H NMR (400 MHz, MeOH-d₄) δ 8.76-8.61 (m, 2H),8.56-8.45 (m, 2H), 7.79-7.68 (m, 3H), 5.18-5.05 (m, 1H), 4.12 (s, 3H),3.36 (d, J = 1.5 Hz, 6H), 2.63 (s, 3H), 1.45 (d, J = 6.4 Hz, 6H). 608

I-72 — 620.12 Ortho- gonal HPLC method B Injection 2, 2.438 40- 80% 20min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.46 (br. s., 1H), 8.69 (s,1H), 8.54 (s, 1H), 8.40 (br. s., 2H), 8.07-7.89 (m, 2H), 7.80 (s, 1H),5.04 (d, J = 4.9 Hz, 1H), 4.79 (br. s., 1H), 4.06 (s, 4H), 3.68- 3.50(m, 8H), 2.61 (s, 3H), 1.75-1.75 (m, 1H), 1.35 (d, J = 6.4 Hz, 6H). 609

I-67 — 605.16 Ortho- gonal HPLC method B Injection 2, 2.362 20- 100% 15min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 9.88 (br. s., 1H), 8.67 (s,1H), 8.51 (s, 1H), 8.41 (br. s., 1H), 8.01-7.86 (m, 4H), 7.78 (s, 1H),5.25 (br. s., 1H), 4.55-4.19 (m, 4H), 4.16-3.99 (m, 5H), 3.62- 3.52 (m,3H), 2.60 (s, 3H), 1.42 (d, J = 6.1 Hz, 3H). 610

I-67 — 577.17 Ortho- gonal HPLC method B Injection 2, 2.056 20- 100% 20min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ 10.36 (s, 1H), 8.72 (s, 1H),8.56 (d, J = 1.7 Hz, 1H), 8.38 (br. s., 1H), 8.06-7.91 (m, 3H),7.87-7.78 (m, 2H), 5.24 (td, J = 6.3, 3.4 Hz, 1H), 4.43-4.22 (m, 2H),4.08 (s, 3H), 3.90 (s, 3H), 1.42 (d, J = 6.3 Hz, 3H). 611

I-67 I-119 550.20 2.155 45- 95% 13 min, 100% 6 min ¹H NMR (500 MHz,DMSO-d₆) δ 9.96-9.57 (m, 1H), 8.75 (s, 1H), 8.62-8.49 (m, 2H), 8.10-7.94 (m, 2H), 7.84 (s, 1H), 7.81-7.74 (m, 1H), 7.19 (d, J = 8.5 Hz, 1H),5.32-5.15 (m, 1H), 4.67-4.53 (m, 1H), 4.41-4.23 (m, 2H), 4.13-4.05 (m,3H), 3.69 (t, J = 6.9 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H), 2.66-2.59 (m,3H), 1.42 (d, J = 6.6 Hz, 3H).

Example 612(2S,3S)-3-((5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-ol

This intermediate was prepared from (2R,3S)-butane-2,3-diol using thesame synthetic sequence as described for Intermediate I-72. LC-MS:Method H, RT=1.21 min, MS (ESI) m/z: 414.0 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.70-8.62 (m, 1H), 8.58 (s, 1H), 7.90-7.83 (m, 1H), 7.82-7.77(m, 1H), 7.60-7.45 (m, 1H), 4.36-4.19 (m, 1H), 4.16 (s, 3H), 4.05-3.87(m, 1H), 2.68 (s, 3H), 2.65-2.58 (m, 1H), 1.38 (d, J=6.4 Hz, 3H), 1.34(d, J=6.4 Hz, 3H).

Example 613(2R,3S)-3-((2-(2-carbamoyl-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-75 was dissolved in a 7 M ammonia solution in MeOH (2 mL,92 mmol) and the resulting mixture stirred for 12 h at 65° C. Thereaction mixture was then concentrated and purified by reverse phaseHPLC (Method D, 30-70% 20 min, 100% 5 min) to yield Example 613 (8.4 mg,0.014 mmol, 74% yield). LC-MS: Method H, RT=0.99 min, MS (ESI) m/z:562.20 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.52 (s, 1H), 8.87 (s, 1H),8.73 (br. s., 2H), 8.44 (s, 1H), 8.19-7.73 (m, 4H), 5.12 (dd, J=6.4, 2.4Hz, 1H), 4.83 (dd, J=6.3, 2.6 Hz, 1H), 3.48-3.26 (m, 2H), 2.71 (s, 3H),1.41 (t, J=6.4 Hz, 7H).

Example 614(2R,3S)-3-((5-fluoro-2-(7-methyl-2-(methylcarbamoyl)quinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Example 614 was prepared from methylamine (33% in EtOH) using the methoddescribed for Example 613. LC-MS: Method H, RT=0.99 min, MS (ESI) m/z:576.18 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.48 (s, 1H), 9.07 (d, J=4.9Hz, 1H), 8.83 (s, 1H), 8.73 (br. s., 2H), 8.11-8.01 (m, 2H), 7.94 (d,J=11.6 Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.83 (d, J=4.3 Hz, 1H),2.98-2.90 (m, 3H), 2.70 (s, 3H), 2.52 (br. s., 3H), 1.40 (t, J=6.9 Hz,6H).

Example 615(2R,3S)-3-((2-(2-(dimethylcarbamoyl)-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Example 615 was prepared from dimethylamine (2M in THF) using the methodas described for Example 613. LC-MS: Method H, RT=0.99 min, MS (ESI)m/z: 590.20 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.96 (br. s., 1H), 9.19(s, 1H), 8.84 (s, 1H), 8.72 (br. s., 2H), 8.09-8.03 (m, 2H), 7.96 (d,J=11.3 Hz, 1H), 5.12 (d, J=6.1 Hz, 1H), 4.82 (d, J=5.5 Hz, 1H),3.26-3.07 (m, 6H), 2.69 (s, 3H), 1.40 (t, J=6.4 Hz, 6H).

Example 616(2R,3S)-3-((5-fluoro-2-(2-((2-hydroxyethyl)carbamoyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Example 616 was prepared from 2-aminoethanol using the same method asdescribed for Example 613. LC-MS: Method H, RT=1.09 min, MS (ESI) m/z:606.0 (M+H)⁺.

Preparation of Alcohol Examples

The alcohols in the accompanying table were prepared according to thefollowing three general procedures.

Primary Alcohols

The appropriately substituted hetero-aryl ester was subjected toconditions described in Procedure G. Purification by Prep HPLC (MethodD) afforded the desired example.

Secondary Alcohols

The appropriately substituted hetero-aryl aldehyde was subjected toconditions described in Procedure H. Purification by Prep HPLC (MethodD) afforded the desired example.

Tertiary Alcohols

The appropriately substituted hetero-aryl ester was subjected toconditions described in Procedure H. Purification by Prep HPLC (MethodD) afforded the desired example.

Orthog- onal HPLC HPLC Ester/ LCMS method B Prep Ex. Alde- [M + H]⁺Injection Method No. Structure hyde m/z 2 D NMR 617

I-118 564.0 2.037 45-90% 20 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ9.89 (br. s., 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.51 (br. s., 1H), 8.15(s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.89 (br.s., 1H), 7.82 (s, 1H), 5.33 (t, J = 5.6 Hz, 1H), 5.19-5.03 (m, J = 6.6,2.6 Hz, 1H), 4.83- 4.73 (m, 1H), 4.49 (d, J = 5.5 Hz, 2H), 4.09 (s, 3H),2.63 (s, 3H), 1.41 (t, J = 6.3 Hz, 6H) 618

I-74 592.1 2.126 45-90% 12 min, 100% 5 min ¹H NMR (500 MHz, DMSO-d₆) δ9.82 (br. s., 1H), 8.69 (s, 1H), 8.56-8.48 (m, 2H), 8.02 (d, J = 8.2 Hz,1H), 7.94 (d, J = 11.6 Hz, 1H), 7.83 (br. s., 1H), 7.79 (s, 1H), 7.55(d, J = 8.5 Hz, 1H), 5.11 (d, J = 5.5 Hz, 1H), 4.79 (d, J = 6.1 Hz, 1H),4.07 (s, 3H), 2.61 (s, 3H), 1.43-1.37 (m, 12H) 619

I-85 564.1 2.092 55-85% 25 min, 85% 4 min ¹H NMR (500 MHz, DMSO-d₆) δ10.18 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.27 (d, J = 5.5 Hz, 1H),8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 7.62(s, 1H), 7.34 (d, J = 4.0 Hz, 1H), 5.14 (dd, J = 6.4, 2.7 Hz, 1H), 4.80(dd, J = 6.4, 2.7 Hz, 1H), 4.49 (d, J = 4.6 Hz, 2H), 4.08 (s, 3H), 2.63(s, 3H), 1.41 (t, J = 6.0 Hz, 6H) 620

I-120 579.2 2.384 45-90% 20 min, 100% 7 min ¹H NMR (500 MHz, DMSO-d₆) δ10.04 (br. s., 1H), 8.83 (br. s., 2H), 8.72 (s, 1H), 8.56 (s, 1H), 8.04(d, J = 8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.82 (s, 1H), 5.14 (d, J= 5.2 Hz, 1H), 4.82 (d, J = 3.7 Hz, 1H), 4.76-4.66 (m, 1H), 4.09 (s,3H), 3.40-3.37 (m, 1H), 2.63 (s, 3H), 1.41 (dd, J = 6.0, 4.1 Hz, 6H),1.36 (d, J = 6.4 Hz, 3H)

Example 6212-((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethylisothiazol-5-ylcarbamate

Example 318 (12 mg, 0.029 mmol), isothiazole-5-carboxylic acid (7.38 mg,0.057 mmol) and triethylamine (7.97 μl, 0.057 mmol) were suspended intoluene (1 mL) in a pressure rated 1 dram vial. Diphenylphosphoryl azide(15.73 mg, 0.057 mmol) was added to the mixture which was heated to 110°C. for 3 hours. The crude reaction mixture was purified by reverse phaseHPLC (Method D, 65-100% 20 min, 100% 5 min) to yield Example 621 (1.3mg, 2.38 mmol, 8% yield). LC-MS: Method H, RT=1.25 min, MS (ESI) m/z:546.10 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.62 (s, 1H),8.21 (s, 1H), 8.02-8.12 (m, 1H), 7.88 (s, 1H), 6.81 (s, 1H), 4.61-4.69(m, 2H), 4.46-4.56 (m, 2H), 4.10 (s, 3H), 3.19 (s, 3H).

Example 622(R)-5-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)methyl)oxazolidin-2-one

Intermediate 622A: (R)-5-(chloromethyl)oxazolidin-2-one

(R)-2-(chloromethyl)oxirane (285 mg, 3.08 mmol), potassium cyanate (500mg, 6.16 mmol) and magnesium sulfate (742 mg, 6.16 mmol) were dissolvedin water (10 mL) and the mixture was heated to 100° C. under a refluxcondenser for 18 h. The reaction mixture was then diluted with water andextracted with EtOAc (3×). The combined organic layer was washed withbrine, dried with sodium sulfate, filtered and concentrated to yieldIntermediate 622A (210 mg, 1.549 mmol, 50.3% yield). The product wasbrought forward without further purification. ¹H NMR (400 MHz, CDCl₃) δ5.81 (br. s., 1H), 4.98-4.75 (m, 1H), 3.84-3.65 (m, 3H), 3.57 (ddd,J=9.0, 5.9, 1.0 Hz, 1H).

Example 622

Intermediate I-65 (30 mg, 0.080 mmol) was dissolved in DMF (2 mL) alongwith potassium carbonate (33.1 mg, 0.239 mmol), Intermediate 622A (21.64mg, 0.160 mmol) and potassium iodide (13.25 mg, 0.080 mmol). Thereaction mixture was then stirred at 80° C. for 18 h before beingdiluted with EtOAc. The organic layer was washed with 10% aq. LiCl (3×),brine, dried with sodium sulfate, filtered, and concentrated. The cruderesidue was purified by reverse phase HPLC (Method D, 30-75% 30 min,100% 5 min) to yield Example 622 (4 mg, 8.00 μmol, 10.02% yield). LC-MS:Method H, RT=1.17 min, MS (ESI) m/z: 475.05 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.75 (s, 1H), 8.60 (s, 1H), 7.99-8.08 (m, 1H), 7.87 (s, 1H),7.59-7.69 (m, 1H), 4.93-5.09 (m, 1H), 4.27-4.49 (m, 2H), 4.09 (s, 3H),3.48-3.72 (m, 1H), 3.36-3.45 (m, 1H), 2.65 (s, 3H).

Example 6234-(((4-chloro-5-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)methyl)oxazol-2-amine

Intermediate 623A: 1-bromo-3-((tert-butyldimethylsilyl)oxy)propan-2-one

1-bromo-3-((tert-butyldimethylsilyl)oxy)propan-2-ol (500 mg, 1.857 mmol)was dissolved in DCM (10 mL). Dess-Martin Periodinane (1181 mg, 2.79mmol) was added to the reaction mixture which stirred at roomtemperature for 2 hours. The reaction mixture was concentrated and theresulting residue was dissolved in a small amount of methylene chloridebefore being charged to a 12 g silica gel cartridge which was elutedwith a 15 min gradient from 0-100% EtOAc in hexane. Fractions containingthe desired product were collected and concentrated to yieldIntermediate 623A (300 mg, 1.123 mmol, 60.5% yield) as a clear oil. ¹HNMR (400 MHz, CDCl₃) δ 4.25 (s, 2H), 3.94-4.05 (m, 2H), 0.75-0.89 (m,9H), −0.10-0.09 (m, 6H).

Example 623

Intermediate 623A (20 mg, 0.053 mmol) was dissolved in DMF (2 mL).Potassium carbonate (22.07 mg, 0.160 mmol) was added to the mixturefollowed by I-65 (20 mg, 0.053 mmol). The reaction mixture was stirredfor 1 h at room temperature after which additional Intermediate 623A (20mg, 0.053 mmol) was added to the mixture. The reaction mixture wasallowed to stir for 2 hours at room temperature and then quenched with afew drops of AcOH. The mixture was diluted with EtOAc and the organiclayer was washed with 10% aq. LiCl (3×), brine, dried with sodiumsulfate, filtered and concentrated. The resulting residue was dissolvedin THF (5 mL)/water (0.500 mL)/acetic acid (0.500 mL). 1M TBAF in THF(0.064 mL, 0.064 mmol) was added to the mixture which was allowed tostir for 1 hour at room temperature after which additional 1M TBAF inTHF (0.064 mL, 0.064 mmol) was added. The mixture was then diluted 1.5 Mdipotassium phosphate solution and extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried with sodium sulfate,filtered and concentrated. The resulting residue was dissolved in THF (1mL) along with cyanamide (21.59 mg, 0.514 mmol), 1N aqueous sodiumacetate (0.051 mL, 0.051 mmol), tetrabutylammonium hydroxide (13.33 mg,0.051 mmol) and 1M aq. NaOH (0.051 mL, 0.051 mmol). The reaction mixturewas allowed to stir at room temperature for 3 h then a few drops of AcOHadded and the reaction mixture was concentrated and purified by reversephase HPLC (Method D, 40-73% 22 min, 100% 7 min) to yield Example 623(0.6 mg, 0.001 mmol, 2% yield) over the three step sequence. LC-MS:Method H, RT=1.05 min, MS (ESI) m/z: 472.10 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.76 (s, 1H), 8.61 (s, 1H), 8.10-8.14 (m, 1H), 7.81-7.90 (m,1H), 7.56 (s, 1H), 6.66 (s, 2H), 5.02 (s, 2H), 4.10 (s, 3H), 2.66 (s,3H).

Example 624(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(2-(phosphonooxy)ethyl)pyrimidin-5-yl)carbamate

Intermediate 624A:(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(2-((bis(2-(trimethylsilyl)ethoxy)phosphoryl)oxy)ethyl)pyrimidin-5-yl)carbamate

To a suspension of Example 566 (313 mg, 0.528 mmol) in DCM (40 mL) wasadded bis(2-(trimethylsilyl)ethyl) diisopropylphosphoramidite (0.7 mL,1.704 mmol) followed by 1H-tetrazole (137 mg, 1.956 mmol) and theresulting mixture was stirred for 30 minutes at room temperature. Thereaction mixture was then cooled to 0° C. and hydrogen peroxide (35% wt.in H₂O) (0.3 mL, 3.43 mmol) was added dropwise over 2 minutes. Afterstirring for 30 minutes at rt, the reaction mixture was diluted with 30mL of DCM and the organic layer was washed with saturated aqueous sodiumsulfite (2×), brine (1×), dried with sodium sulfate, filtered andconcentrated. The resulting residue was dissolved in a small amount ofDCM and purified by silica gel chromatography (gradient of 0-100%EtOAc/DCM). The fractions containing desired product were concentratedto yield Intermediate 624A (349 mg, 0.4 mmol, 76% yield). LC-MS: MethodH, MS (ESI) m/z: 873.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (br. s.,2H), 8.53 (d, J=2.0 Hz, 1H), 8.46 (s, 1H), 7.77 (d, J=11.4 Hz, 1H), 7.69(dd, J=2.0, 0.9 Hz, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.39-7.30 (m, 1H),5.21-4.99 (m, 1H), 4.60-4.44 (m, 5H), 4.16-3.98 (m, 4H), 3.28 (t, J=6.8Hz, 2H), 1.48 (t, J=7.0 Hz, 3H), 1.42 (dd, J=16.3, 6.4 Hz, 6H),1.10-0.98 (m, J=8.6, 8.6, 0.7 Hz, 4H), 0.03-0.04 (m, 18H).

Example 624

Intermediate 624A (226 mg, 0.259 mmol) was dissolved in DCM (10 mL). TFA(0.140 mL, 1.812 mmol) and water (0.033 mL, 1.812 mmol) were added tothe solution which was stirred at room temperature. After 5 minutes ofstirring, additional TFA (0.140 mL, 1.812 mmol) was added dropwise andthe reaction mixture was allowed to stir for 50 minutes at roomtemperature. Concentration of the reaction mixture followed bytrituration from ether yielded a particulate solid. The mother liquorwas removed by filtration, and the remaining solid was redissolved indioxane and concentrated to afford 624 in quantitative yield. LC-MS:Method H, RT=1.10 min, MS (ESI) m/z: 673.2 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 10.03 (br. s., 1H), 8.78 (br. s., 2H), 8.68 (s, 1H), 8.54 (d,J=1.8 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.94 (d, J=11.7 Hz, 1H), 7.78(dd, J=2.0, 0.9 Hz, 1H), 5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.78 (dd, J=6.4,2.9 Hz, 1H), 4.51 (q, J=7.0 Hz, 2H), 4.23 (q, J=6.8 Hz, 2H), 3.10 (t,J=6.7 Hz, 2H), 2.60 (s, 3H), 1.46-1.29 (m, 9H).

Example 6252-(6-chloro-3-(methoxymethyl)quinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole

Intermediate 625A: 8-bromo-6-chloro-3-(methoxymethyl)quinoline

Intermediate I-123 (33.5 mg, 0.143 mmol), 3-methoxypropanal (13.8 mg,0.157 mmol), and sodium methoxide (0.5 M in MeOH, 314 μl, 0.157 mmol)were dissolved in MeOH (1.43 mL) and heated to reflux. After 3 hours,the reaction mixture was diluted with saturated NH₄Cl and EtOAc. Thelayers were separated and the organic layer was washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 24 g silica gel column, 19minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate625A (23.5 mg, 0.082 mmol, 57%) as a yellow solid: ¹H NMR (400 MHz,CDCl₃) δ 8.99 (d, J=2.2 Hz, 1H), 8.09-8.07 (m, 1H), 8.04 (d, J=2.2 Hz,1H), 7.82 (d, J=2.2 Hz, 1H), 4.71 (s, 2H), 3.51 (s, 3H); LC-MS: MethodH, RT=1.19 min, MS (ESI) m/z: 286/288 (M+H)⁺.

Intermediate 625B: (6-chloro-3-(methoxymethyl)quinolin-8-yl)boronic acid

Intermediate 625A (73.2 mg, 0.255 mmol), bispinacolatodiboron (97 mg,0.383 mmol), and potassium acetate (62.7 mg, 0.639 mmol) were dissolvedin 1,4-dioxane (2.56 mL) and degassed for 5 minutes by bubbling withargon. PdCl₂(dppf)-CH₂Cl₂Adduct (16.7 mg, 0.020 mmol) was added and thereaction degassed for an additional 10 minutes. The reaction mixture washeated to 130° C. in the microwave for 45 minutes. The reaction mixturewas diluted with EtOAc and water. The aqueous layer was furtherextracted twice with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crudematerial was purified by preparative HPLC (Method A, 30-100% B in 15minutes) to give Intermediate 625B (31.4 mg, 0.125 mmol, 49%) was abrown solid: LC-MS: Method H, RT=0.97 min, MS (ESI) m/z: 252.1 (M+H)⁺.

Example 625

Intermediate 625B (10 mg, 0.040 mmol), Intermediate I-3 (12.32 mg, 0.048mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (1.95 mg, 2.39 μmol) were dissolvedin 1,4-dioxane (306 μL) and Na₂CO₃ (2 M, 179 μL, 0.358 mmol) and heatedto 100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature, diluted with EtOAc, washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by preparative HPLC (Method D, 60-100% B in 20 minutes) to giveExample 625 (7.0 mg, 0.018 mmol, 46%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.09(br. s., 1H), 8.84 (br. s., 1H), 8.45 (br. s., 1H), 8.33 (br. s., 1H),7.56 (br. s., 1H), 7.02 (br. s., 1H), 4.74 (s, 2H), 3.87 (s, 3H), 3.44(s, 3H), 2.76 (s, 3H); LC-MS: Method H, RT=1.44 min, MS (ESI) m/z: 385.1(M+H)⁺; Analytical HPLC Method B, 100% purity.

Example 6262-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole

Intermediate 626A:6-methoxy-4-methyl-2-(tributylstannyl)benzo[d]thiazole

Intermediate I-3 (300 mg, 1.162 mmol) was dissolved in Et₂O (4.65 mL)and cooled to −78° C. BuLi (2.5 M in hexanes, 511 μL, 1.278 mmol) wasthen added. After 45 minutes, tributylchlorostannane (315 μL, 1.16 mmol)was added. After 15 minutes, the reaction mixture was warmed to ambienttemperature and concentrated in vacuo. The crude material was suspendedin hexanes and filtered through dry celite. The residue was concentratedin vacuo to give Intermediate 626A, which was used directly in thesubsequent step.

Intermediate 626B:2-(3-(benzyloxy)-6-chloroquinolin-8-yl)-6-methoxy-4-methylbenzo[d]thiazole

Intermediate I-122A (270 mg, 0.774 mmol), Intermediate 626A (526 mg,1.12 mmol), and potassium acetate (152 mg, 1.55 mmol) were dissolved in1,4-dioxane (7.74 mL) and degassed by bubbling with argon for 15minutes. Palladium tetrakistriphenylphosphine (44.7 mg, 0.039 mmol) wasadded and the reaction vessel was sealed and heated to 120° C. in themicrowave for 2 hours. The reaction mixture was diluted with EtOAc,washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0to 100% EtOAc in hexanes) then repurified by column chromatography(ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% DCM inhexanes) to give Intermediate 626B (201 mg, 0.45 mmol, 58%) as a yellowsolid: ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J=2.9 Hz, 1H), 8.86 (d, J=2.4Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.56-7.38 (m, 6H), 7.28 (s, 1H), 6.96(dd, J=2.6, 0.9 Hz, 1H), 5.27 (s, 2H), 3.92 (s, 3H), 2.85 (s, 3H);LC-MS: Method H, RT=1.58 min, MS (ESI) m/z: 447.1 (M+H)⁺.

Intermediate 626C:6-chloro-8-(6-methoxy-4-methylbenzo[d]thiazol-2-yl)quinolin-3-ol

Intermediate 626B (25 mg, 0.056 mmol) and pentamethylbenzene (58.0 mg,0.392 mmol) were dissolved in DCM (2.8 mL) and cooled to −78° C. Borontrichloride (1 M in heptane, 145 μL, 0.145 mmol) was added and thereaction mixture was allowed to slowly warm to ambient temperature.After stirring overnight, the reaction was quenched with 1 N HCl andextracted thrice with EtOAc. The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 4 g silicagel column, 15 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 626C (17.1 mg, 0.048 mmol, 86%) as a yellow solid: ¹H NMR(400 MHz, CDCl₃) δ 8.87 (d, J=2.4 Hz, 1H), 8.82 (d, J=2.9 Hz, 1H), 7.77(d, J=2.2 Hz, 1H), 7.48 (d, J=2.9 Hz, 1H), 6.96 (dd, J=2.6, 0.9 Hz, 1H),3.92 (s, 3H), 2.86 (s, 3H); LC-MS: Method H, RT=1.39 min, MS (ESI) m/z:357.1 (M+H)⁺.

Example 626

Intermediate 626C (17 mg, 0.048 mmol), K₂CO₃ (13.2 mg, 0.095 mmol), andMeI (11.9 μL, 0.191 mmol) were dissolved in acetone (1.91 mL). Afterstirring overnight, the reaction mixture was concentrated in vacuo andpurified by preparative HPLC (Method D, 55-95% B in 10 minutes) to giveExample 626 (5.5 mg, 0.015 mmol, 31%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.89(br. s., 1H), 8.67 (s, 1H), 8.18 (s, 1H), 7.95 (br. s., 1H), 7.54 (s,1H), 7.01 (br. s., 1H), 4.00 (s, 3H), 3.86 (s, 3H), 2.75 (s, 3H); LC-MS:Method H, RT=1.51 min, MS (ESI) m/z: 371.1 (M+H)⁺; Analytical HPLCMethod B, 100% purity.

Example 6272-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)propan-2-ol

Intermediate 627A: 2-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)propan-2-ol

Intermediate I-20C (50 mg, 0.165 mmol) was dissolved in THF (331 μL) andcooled to −78° C. Methylmagnesium bromide (3 M in Et₂O, 124 μL, 0.372mmol) was added and the reaction mixture was allowed to slowly warm to0° C. in the freezer. After stirring overnight, the reaction wasquenched with saturated NH₄Cl and extracted with EtOAc. The organiclayer was washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate 627A (13.6 mg, 0.045mmol, 27%) as a clear oil: LC-MS: Method H, RT=1.00 min, MS (ESI) m/z:302/304 (M+H)⁺.

Example 627

Intermediate I-9 (11.6 mg, 0.039 mmol), Intermediate 627A (14 mg, 0.046mmol), and potassium phosphate, tribasic (16.4 mg, 0.077 mmol) weredissolved in DMF (386 μL) and degassed by bubbling with argon for 15minutes. Palladium tetrakistriphenylphosphine (4.46 mg, 3.86 μmol) wasadded and degassing continued for 5 minutes. The reaction was thensealed and heated to 85° C. After stirring overnight, the crude materialwas purified by preparative HPLC (Method D, 50-100% B in 14 minutes) togive Example 627 (6.6 mg, 0.016 mmol, 42%): ¹H NMR (500 MHz, DMSO-d₆) δ8.75 (s, 1H), 8.51 (d, J=1.7 Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H), 7.59(d, J=2.5 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 5.42 (s, 1H), 4.10 (s, 3H),3.88 (s, 3H), 2.66 (s, 3H), 1.83 (s, 6H); LC-MS: Method H, RT=1.27 min,MS (ESI) m/z: 396.2 (M+H)⁺; Analytical HPLC Method B, 97% purity.

Example 6281-(6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 628A:1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) andcooled to −78° C. tert-Butylmagnesium chloride (1 M in THF, 184 μL,0.184 mmol) was then added and the reaction mixture was allowed toslowly warm to 0° C. in the freezer. After stirring overnight, thereaction was quenched with saturated NH₄Cl and extracted with EtOAc. Theorganic layer was washed with water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 12 g silica gel column, 17 minute gradientfrom 0 to 100% EtOAc in hexanes) to give Intermediate 628A (29 mg, 0.088mmol, 60%) as a white solid: LC-MS: Method H, RT=1.10 min, MS (ESI) m/z:330/332 (M+H)⁺.

Example 628

Intermediate I-2 (16.6 mg, 0.053 mmol), Intermediate 628A (14.5 mg,0.044 mmol), and potassium phosphate, tribasic (18.6 mg, 0.088 mmol)were dissolved in DMF (439 μL) and degassed by bubbling with argon for15 minutes. Palladium tetrakistriphenylphosphine (5.07 mg, 4.39 μmol)was added and degassing continued for 5 minutes. The reaction vessel wasthen sealed and heated to 85° C. After heating overnight, the crudematerial was purified by preparative HPLC (Method D, 45-85% B in 20minutes) to give Example 628 (6.4 mg, 0.015 mmol, 33%): ¹H NMR (500 MHz,DMSO-d₆) δ 9.11 (s, 1H), 8.77 (d, J=1.9 Hz, 1H), 8.05 (s, 1H), 7.65 (d,J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.45 (d, J=4.7 Hz, 1H), 5.34 (d,J=4.7 Hz, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.48 (s, 3H), 2.72 (s, 3H),0.97 (s, 9H); LC-MS: Method H, RT=1.24 min, MS (ESI) m/z: 437.8 (M+H)⁺;Analytical HPLC Method B, 98% purity.

Example 629(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(phenyl)methanol

Intermediate 629A:(2-bromo-6-methoxybenzo[d]thiazol-4-yl)(phenyl)methanol

Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) andcooled to −78° C. Phenylmagnesium bromide (3 M in Et₂O, 61.2 μl, 0.184mmol) was added and the reaction mixture was allowed to slowly warm to0° C. in the freezer. After stirring overnight, the reaction wasquenched with saturated NH₄Cl and extracted with EtOAc. The organiclayer was washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate 629A (33.6 mg, 0.096mmol, 65%) as a white solid: LC-MS: Method H, RT=1.01 min, MS (ESI) m/z:350/352 (M+H)⁺.

Example 629

Intermediate I-9 (14.1 mg, 0.047 mmol), Intermediate 629A (16.5 mg,0.047 mmol), and potassium phosphate, tribasic (20 mg, 0.094 mmol) weredissolved in DMF (471 μL) and degassed by bubbling with argon for 15minutes. Palladium tetrakistriphenylphosphine (5.44 mg, 4.71 μmol) wasadded and degassing continued for 5 minutes. The reaction vessel wasthen sealed and heated to 85° C. After heating overnight, the crudematerial was purified by preparative HPLC (Method D, 40-75% B in 15minutes) then repurified by preparative HPLC (Method D, 60-100% B in 12minutes) to give Example 629 (7.4 mg, 0.017 mmol, 35%): ¹H NMR (500 MHz,DMSO-d₆) δ 8.74 (s, 1H), 8.61 (d, J=1.7 Hz, 1H), 7.83 (s, 1H), 7.62-7.55(m, 3H), 7.35-7.26 (m, 3H), 7.23-7.15 (m, 1H), 6.70 (d, J=4.4 Hz, 1H),6.10 (d, J=4.1 Hz, 1H), 4.09 (s, 3H), 3.86 (s, 3H), 2.67 (s, 3H); LC-MS:Method H, RT=1.24 min, MS (ESI) m/z: 443.8 (M+H)⁺; Analytical HPLCMethod B, 99% purity.

Example 6301-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate I-9 (15.8 mg, 0.053 mmol), Intermediate 628A (14.5 mg,0.044 mmol), and potassium phosphate, tribasic (18.6 mg, 0.088 mmol)were dissolved in DMF (439 μL) and degassed by bubbling with argon for15 minutes. Palladium tetrakistriphenylphosphine (5.07 mg, 4.39 μmol)was added and degassing continued for 5 minutes. The reaction vessel wasthen sealed and heated to 85° C. After heating overnight, the crudematerial was purified by preparative HPLC (Method D, 50-85% B in 15minutes) then repurified by preparative HPLC (Method D, 60-100% B in 20minutes) to give Example 630 (3.8 mg, 0.0087 mmol, 20%): ¹H NMR (500MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.55 (d, J=1.7 Hz, 1H), 7.83 (s, 1H), 7.61(d, J=2.5 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 5.43 (s, 1H), 5.34 (br. s.,1H), 4.09 (s, 3H), 3.88 (s, 3H), 2.66 (s, 3H), 0.96 (s, 9H); LC-MS:Method H, RT=1.32 min, MS (ESI) m/z: 423.8 (M+H)⁺; Analytical HPLCMethod B, 97% purity.

Example 6311-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2-phenylethanol

Intermediate 631A:1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2-phenylethanol

Intermediate I-20 (40 mg, 0.147 mmol) was dissolved in THF (294 μL) andcooled to −78° C. Benzylmagnesium chloride (2 M in Et₂O, 92 μL, 0.184mmol) was added and the reaction mixture was allowed to slowly warm to0° C. in the freezer. After stirring overnight, the reaction wasquenched with saturated NH₄Cl and extracted with EtOAc. The organiclayer was washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate 631A (18.9 mg, 0.052mmol, 35%) as a yellow oil: LC-MS: Method H, RT=1.07 min, MS (ESI) m/z:364/366 (M+H)⁺.

Example 631

Intermediate I-9 (9.39 mg, 0.031 mmol), Intermediate 631A (9.5 mg, 0.026mmol), and potassium phosphate, tribasic (11.1 mg, 0.052 mmol) weredissolved in DMF (261 μL) and degassed by bubbling with argon for 15minutes. Palladium tetrakistriphenylphosphine (3.01 mg, 2.61 μmol) wasadded and degassing continued for 5 minutes. The reaction was thensealed and heated to 85° C. After heating overnight, the crude materialwas purified by preparative HPLC (Method D, 45-80% B in 20 minutes) thenrepurified by preparative HPLC (Method D, 70-100% B in 15 minutes) togive Example 631 (1.2 mg, 0.0026 mmol, 10%): ¹H NMR (500 MHz, DMSO-d₆) δ8.76 (s, 1H), 8.61 (d, J=1.4 Hz, 1H), 7.85 (s, 1H), 7.60 (d, J=2.5 Hz,1H), 7.38-7.33 (m, 2H), 7.33-7.27 (m, 2H), 7.23-7.16 (m, 2H), 5.71 (dt,J=8.3, 4.4 Hz, 1H), 5.49 (d, J=5.2 Hz, 1H), 4.10 (s, 3H), 3.87 (s, 3H),3.29 (dd, J=13.5, 3.6 Hz, 1H), 2.97 (dd, J=13.6, 8.4 Hz, 1H), 2.69 (s,3H); LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 457.8 (M+H)⁺;Analytical HPLC Method B, 100% purity.

Example 6321-(5-fluoro-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 632A:1-(2-amino-5-fluoro-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate I-43C (100 mg, 0.430 mmol) was dissolved in THF (4.3 mL).

Sodium hydride (18.9 mg, 0.473 mmol) was then added. After 30 minutes,the reaction mixture was cooled to −78° C. and tert-butyllithium (1 M,430 μL, 0.516 mmol) was added. After 45 minutes, pivalaldehyde (96 μL,0.86 mmol) was added and the reaction mixture was allowed to warm toambient temperature. After the reaction mixture achieved ambienttemperature, it was diluted with EtOAc and washed with water, thenbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo to giveIntermediate 632A, which was used immediately in the subsequentreaction: LC-MS: Method H, RT=0.74 min, MS (ESI) m/z: 285.2 (M+H)⁺.

Intermediate 632B:1-(2-chloro-5-fluoro-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Copper(II) chloride (81 mg, 0.601 mmol) and t-butyl nitrite (77 μL,0.644 mmol) were dissolved in MeCN (1.72 mL) and allowed to stir 10minutes. Intermediate 632A (122 mg, 0.429 mmol) was dissolved in MeCN(2.57 mL) and the copper solution was added and heated to 60° C. After1.5 hours, the reaction mixture was diluted with EtOAc, washed with 1 NHCl, saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 12 g silica gel column, 17 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate 632B (21 mg, 0.021 mmol,4.8%) as a brown solid: LC-MS: Method H, RT=1.14 min, MS (ESI) m/z:304.1 (M+H)⁺.

Example 632

Intermediate I-9 (24.9 mg, 0.083 mmol) and Intermediate 632B (21 mg,0.069 mmol) were dissolved in DMF (691 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(3.39 mg, 4.15 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 41.5 μl,0.083 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 100° C. in the microwave for 30minutes. The material was heated in the microwave for an additional 30minutes at 120° C. The crude material was purified by preparative HPLC(Method D, 70-100% B in 20 minutes) then repurified by preparative HPLC(Method D, 60-100% B in 20 minutes) to give Example 632 (0.7 mg, 0.0015mmol, 2.2%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.50 (d, J=1.7Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.83-7.80 (m, 1H), 5.57 (br. s., 1H),5.25 (br. s., 1H), 4.08 (s, 3H), 3.94 (s, 3H), 2.64 (s, 3H), 1.00 (s,9H); LC-MS: Method H, RT=1.34 min, MS (ESI) m/z: 442.2 (M+H)⁺;Analytical HPLC Method B, 97% purity.

Example 6332,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol

Intermediate 633A:1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-2,2,2-trifluoroethanol

Intermediate I-21 (207 mg, 0.909 mmol) was dissolved in THF (18.2 mL).(Trifluoromethyl)trimethylsilane (161 μL, 1.09 mmol) then TBAF (1 M inTHF, 1.09 mL, 1.09 mmol) were added to the reaction. After stirringovernight, the reaction mixture was diluted with EtOAc and washed withwater, saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 40 g silica gel column, 19 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate 633A (70.8 mg, 0.238mmol, 26%) as a white solid: LC-MS: Method H, RT=0.98 min, MS (ESI) m/z:298.1 (M+H)⁺.

Intermediate 633B:2,2,2-trifluoro-1-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol(racemic)

Intermediate I-9 (70.6 mg, 0.235 mmol) and Intermediate 633A (70 mg,0.235 mmol) were dissolved in DMF (2.35 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(11.5 mg, 0.014 mmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 141 μL, 0.282 mmol)was added and the reaction degassed for 5 minutes, then sealed andheated to 100° C. in the microwave for 30 minutes. The reaction mixturewas diluted with water and extracted thrice with EtOAc. The combinedorganic layers were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate 633B (racemic) (49.9 mg,0.115 mmol, 49%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s,1H), 8.48 (d, J=1.8 Hz, 1H), 7.78 (d, J=0.9 Hz, 1H), 7.43 (d, J=2.4 Hz,1H), 7.35 (d, J=9.9 Hz, 1H), 7.06 (s, 1H), 5.35 (dd, J=9.8, 7.4 Hz, 1H),4.13 (s, 3H), 3.93 (s, 3H), 2.66 (s, 3H); LC-MS: Method H, RT=1.21 min,MS (ESI) m/z: 436.1 (M+H)⁺.

Example 633

Intermediate 633B (49.9 mg, 0.115 mmol) was purified by chiral SFC(Chiralpak OJ-H, 21×250 mm, 5 micron, 25% IPA/75% CO₂, 2 mL/min) to giveExample 633 (Peak 2, Enantiomer 2, 20.4 mg, 0.044 mmol, 38%, >99% ee) asa yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.48 (d, J=1.5Hz, 1H), 7.78 (dd, J=1.9, 1.0 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.35 (d,J=9.9 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 5.40-5.30 (m, 1H), 4.13 (s, 3H),3.93 (s, 3H), 2.66 (s, 3H); LC-MS: Method H, RT=1.21 min, MS (ESI) m/z:436.1 (M+H)⁺.

Example 6344-(1-fluoro-2,2-dimethylpropyl)-6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 634A:2-bromo-4-(1-fluoro-2,2-dimethylpropyl)-6-methoxybenzo[d]thiazole

Intermediate 628A (20 mg, 0.061 mmol) and Deoxofluor (14 μL, 0.076 mmol)were dissolved in DCM (606 μL). After 1 hour, the reaction mixture wasdiluted with EtOAc and washed with saturated NaHCO₃, water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate634A (24 mg, 0.072 mmol, 100%), which was used immediately in thesubsequent reaction: LC-MS: Method H, RT=1.29 min, MS (ESI) m/z: 332/334(M+H)⁺.

Example 634

Intermediate I-9 (10.8 mg, 0.036 mmol) and Intermediate 634A (10 mg,0.030 mmol) were dissolved in DMF (301 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(1.48 mg, 1.81 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (18.1 μL, 0.036 mmol) wasadded and the reaction degassed for 5 minutes, then sealed and heated to100° C. in the microwave for 30 minutes. The crude material was purifiedby preparative HPLC (Method D, 80-100% B in 15 minutes) to give Example634 (3.5 mg, 0.0079 mmol, 26%): ¹H NMR (500 MHz, CDCl₃) δ 8.50 (s, 1H),8.48 (s, 1H), 7.67 (s, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.11 (d, J=2.2 Hz,1H), 6.37-6.25 (m, 1H), 4.06 (s, 3H), 3.85 (s, 3H), 2.60 (s, 3H), 1.03(s, 9H); LC-MS: Method H, RT=1.47 min, MS (ESI) m/z: 426.2 (M+H)⁺;Analytical HPLC Method B, 96% purity.

Example 6354-(benzyloxy)-6-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)benzo[d]thiazole

Intermediate 635A: 2-(benzyloxy)-4-methoxy-1-nitrobenzene

5-Methoxy-2-nitrophenol (1 g, 5.91 mmol), potassium carbonate (2.45 g,17.7 mmol), and benzyl bromide (1.06 ml, 8.87 mmol) were dissolved inDMF (11.8 mL). After stirring overnight, the reaction mixture wasdiluted with water and extracted twice with EtOAc. The combined organiclayers were washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 120 g silica gel column, 29 minute gradient from 0to 100% EtOAc in hexanes) to give Intermediate 635A (1.51 g, 5.81 mmol,98%) as a light yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J=9.0 Hz,1H), 7.52-7.46 (m, 2H), 7.43-7.37 (m, 2H), 7.36-7.30 (m, 1H), 6.57 (d,J=2.4 Hz, 1H), 6.52 (dd, J=9.1, 2.5 Hz, 1H), 5.22 (s, 2H), 3.84 (s, 3H);LC-MS: Method H, The compound did not ionize.

Intermediate 635B: 2-(benzyloxy)-4-methoxyaniline

Intermediate 635A (1.51 g, 5.81 mmol) was dissolved in MeOH (39.7 mL)and THF (4.96 mL). Ammonium chloride (6.21 g, 116 mmol) and zinc (3.80g, 58.1 mmol) were added and the reaction mixture was heated to 40° C.After 3.5 hours, the reaction mixture was concentrated in vacuo. Thecrude material was redissolved in EtOAc/saturated Na₂CO₃ and allowed tostir vigorously for 15 minutes. The mixture was filtered through asintered glass funnel. The organic layer was washed with water thenbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crudematerial was purified by column chromatography (ISCO, 80 g silica gelcolumn, 29 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 635B (511 mg, 2.23 mmol, 38%) as a brown oil: ¹H NMR (400MHz, CDCl₃) δ 7.46-7.31 (m, 5H), 6.68 (d, J=8.4 Hz, 1H), 6.53 (d, J=2.6Hz, 1H), 6.38 (dd, J=8.6, 2.6 Hz, 1H), 5.06 (s, 2H), 3.74 (s, 3H), 3.56(br. s., 2H); LC-MS: Method H, RT=0.69 min, MS (ESI) m/z: 230.2 (M+H)⁺.

Intermediate 635C: 4-(benzyloxy)-6-methoxybenzo[d]thiazol-2-amine

Intermediate 635B (0.5 g, 2.18 mmol) was dissolved in MeCN (10.9 mL).Ammonium thiocyanate (0.249 g, 3.27 mmol) was added, followed bybenzyltrimethylammonium tribromide (0.850 g, 2.18 mmol). After stirringfor 2 days, the reaction mixture was diluted with saturated NaHCO₃ andthe solid collected by suction filtration and washed with water to giveIntermediate 635C (574 mg, 2 mmol, 92%) as a purple solid: LC-MS: MethodH, RT=0.77 min, MS (ESI) m/z: 287.2 (M+H)⁺.

Intermediate 635D: 4-(benzyloxy)-2-chloro-6-methoxybenzo[d]thiazole

Copper(II) chloride (0.377 g, 2.80 mmol) and t-butyl nitrite (0.357 mL,3.00 mmol) were dissolved in MeCN (8 mL) and allowed to stir 10 minutes.Intermediate 635C (0.573 g, 2.001 mmol) was dissolved in MeCN (12 mL)and the copper solution was added and the reaction mixture was heated to60° C. After 2 hours, the reaction mixture was concentrated in vacuo toremove the majority of the MeCN. The reaction was then diluted withEtOAc, washed twice with 1 N HCl, water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 80 g silica gel column, 29 minute gradientfrom 0 to 100% EtOAc in hexanes) to give Intermediate 635D (147 mg,0.481 mmol, 24%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d,J=7.3 Hz, 2H), 7.40-7.34 (m, 2H), 7.32 (d, J=7.3 Hz, 1H), 6.79 (d, J=2.4Hz, 1H), 6.54 (d, J=2.2 Hz, 1H), 5.32 (s, 2H), 3.80 (s, 3H); LC-MS:Method H, RT=1.17 min, MS (ESI) m/z: 306.1 (M+H)⁺.

Example 635

Intermediate I-2 (13.2 mg, 0.042 mmol) and Intermediate 635D (10 mg,0.035 mmol) were dissolved in DMF (350 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(1.72 mg, 2.1 μmol) was added and the reaction degassed by bubbling withargon for 15 minutes. Sodium carbonate (2 M, 21 μL, 0.042 mmol) wasadded and the reaction degassed for 5 minutes, then sealed and heated to100° C. in the microwave for 30 minutes. The crude material was purifiedby preparative HPLC (Method D, 40-80% B in 22 minutes) to give Example635 (7.6 mg, 0.015 mmol, 44%): ¹H NMR (500 MHz, CDCl₃) δ 9.00 (s, 1H),8.85 (br. s., 1H), 7.85 (br. s., 1H), 7.50 (d, J=6.9 Hz, 2H), 7.39-7.22(m, 3H), 6.95 (br. s., 1H), 6.52 (br. s., 1H), 5.38 (s, 2H), 4.77 (s,2H), 3.79 (s, 3H), 3.50 (d, J=1.4 Hz, 3H), 2.61 (br. s., 3H); LC-MS:Method H, RT=1.29 min, MS (ESI) m/z: 458.2 (M+H)⁺; Analytical HPLCMethod B, 93% purity.

Example 6361-(2-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate I-28 (10.4 mg, 0.044 mmol) and Intermediate 628A (12 mg,0.036 mmol) were dissolved in DMF (363 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(1.78 mg, 2.18 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 21.8 μL, 0.044 mmol)was added and the reaction degassed for 5 minutes, then sealed andheated to 100° C. in the microwave for 30 minutes. The crude materialwas purified by preparative HPLC (Method D, 40-100% B in 15 minutes)then repurified by preparative HPLC (Method D, 45-85% B in 22 minutes)to give Example 636 (1.2 mg, 0.0025 mmol, 6.8%): ¹H NMR (500 MHz,DMSO-d₆) δ 8.82 (s, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.05 (d, J=2.2 Hz, 1H),7.62 (d, J=2.2 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 5.41 (br. s., 1H), 5.32(br. s., 1H), 4.10 (s, 3H), 3.88 (s, 3H), 0.95 (s, 9H); LC-MS: Method H,RT=1.43 min, MS (ESI) m/z: 444.2 (M+H)⁺; Analytical HPLC Method B, 91%purity.

Example 6371-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 637A:1-(2-bromo-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 628A (110 mg, 0.333 mmol) was purified by chiralpreparative HPLC (Chiralpak AD, 90% heptane/10% EtOH:MeOH (50:50)) togive Intermediate 637A (33.8 mg, 0.102 mmol, 31%) as a clear oil: ¹H NMR(400 MHz, CDCl₃) δ 7.16 (d, J=2.6 Hz, 1H), 6.98-6.91 (m, 1H), 4.84 (d,J=8.4 Hz, 1H), 4.02 (d, J=8.4 Hz, 1H), 3.86 (s, 3H), 0.96 (s, 9H);LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 330/332 (M+H)⁺.

Example 637

Intermediate I-9 (5.45 mg, 0.018 mmol) and Intermediate 637A (5 mg,0.015 mmol) were dissolved in DMF (151 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(0.742 mg, 0.908 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 9.08 μL, 0.018 mmol)was added and the reaction degassed for 5 minutes, then sealed andheated to 100° C. in the microwave for 30 minutes. The crude materialwas purified by preparative HPLC (Method D, 70-100% B in 15 minutes) togive Example 637 (4.6 mg, 0.011 mmol, 70%): ¹H NMR (500 MHz, DMSO-d₆) δ8.78 (s, 1H), 8.59 (s, 1H), 7.87 (s, 1H), 7.65 (s, 1H), 7.20 (s, 1H),5.48 (d, J=4.6 Hz, 1H), 5.38 (d, J=4.6 Hz, 1H), 4.14 (s, 3H), 3.93 (s,3H), 2.70 (s, 3H), 1.01 (s, 9H); LC-MS: Method H, RT=1.36 min, MS (ESI)m/z: 424.1 (M+H)⁺; Analytical HPLC Method B, 97% purity.

Example 6382-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethyl(5-cyanopyridin-3-yl)carbamate

Intermediate 638A:1-(2-amino-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one

Intermediate I-22 (0.5 g, 1.93 mmol) was dissolved in THF (19.3 mL).Sodium hydride (0.085 g, 2.12 mmol) was added. After 30 minutes, thereaction mixture was cooled to −78° C. and BuLi (1.68 ml, 3.86 mmol) wasadded. After 1 hour, methyl pivalate (0.77 mL, 5.79 mmol) was added andthe reaction mixture was allowed to warm to ambient temperature. Afterachieving ambient temperature, the reaction mixture was diluted withEtOAc and washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0to 20% MeOH in DCM) to give Intermediate 638A (382 mg, 1.45 mmol, 75%)as a brown solid: ¹H NMR (400 MHz, CDCl₃) δ 7.14 (d, J=2.4 Hz, 1H), 6.73(d, J=2.6 Hz, 1H), 5.09 (br. s., 2H), 3.82 (s, 3H), 1.29 (s, 9H); LC-MS:Method H, RT=0.76 min, MS (ESI) m/z: 265.2 (M+H)⁺.

Intermediate 638B:1-(2-amino-6-hydroxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one

Intermediate 638A (380 mg, 1.44 mmol) was dissolved in AcOH (5.75 mL)and HBr (976 μL, 8.63 mmol) and heated to reflux. After heating for 2days, the reaction mixture was concentrated in vacuo to giveIntermediate 638B, which was used directly in the subsequent reaction:LC-MS: Method H, RT=0.64 min, MS (ESI) m/z: 251.1 (M+H)⁺.

Intermediate 638C: 2-((2-amino-4-pivaloylbenzo[d]thiazol-6-yl)oxy)ethylacetate

Intermediate 638B (360 mg, 1.44 mmol), Cs₂CO₃ (2.81 g, 8.63 mmol), and2-bromoethyl acetate (397 μL, 3.60 mmol) were dissolved in DMF (5.75mL). After stirring overnight, the reaction mixture was diluted withwater and extracted thrice with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude material was purified by preparative HPLC (Method A, 30-100% Bin 12 minutes) to give Intermediate 638C (139 mg, 0.412 mmol, 29%) as awhite solid: LC-MS: Method H, RT=0.76 min, MS (ESI) m/z: 337.2 (M+H)⁺.

Intermediate 638D: 2-((2-chloro-4-pivaloylbenzo[d]thiazol-6-yl)oxy)ethylacetate

Copper(II) chloride (78 mg, 0.577 mmol) and t-butyl nitrite (73.5 μL,0.618 mmol) were dissolved in MeCN (1.65 mL) and allowed to stir 10minutes. Intermediate 638C (139 mg, 0.412 mmol) was dissolved in MeCN(2.47 mL) and the copper solution was added and the reaction mixture washeated to 60° C. After 2.5 hours, the reaction mixture was concentratedin vacuo to remove the majority of the MeCN. The reaction was thendiluted with EtOAc, washed twice with 1 N HCl, water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate 638D(134 mg, 0.377 mmol, 91%) as an orange oil: LC-MS: Method H, RT=1.11min, MS (ESI) m/z: 356.1 (M+H)⁺.

Intermediate 638E:1-(2-chloro-6-(2-hydroxyethoxy)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 638D (134 mg, 0.377 mmol) was dissolved in toluene (2.51mL) and THF (1.26 mL) and cooled to −78° C. DIBAL-H (1 M in toluene,1.13 mL, 1.13 mmol) was added and the reaction was warmed to ambienttemperature. After 5 hours, more DIBAL-H (1130 μl, 1.130 mmol) wasadded. After 45 minutes, the reaction was quenched with a saturatedsolution of Rochelle's salt. After stirring overnight, the reactionmixture was extracted with EtOAc. The organic layer was further washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 12 g silicagel column, 17 minute gradient from 0 to 100% EtOAc in hexanes). Theresulting product was purified by chiral preparative HPLC (Chiralpak AD,16% MeOH/EtOH (50/50) in heptane) to give Intermediate 638E (7.2 mg,0.023 mmol, 6.1%) as a clear oil: LC-MS: Method H, RT=0.97 min, MS (ESI)m/z: 316.1 (M+H)⁺.

Intermediate 638F:2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)ethylcarbonochloridate

Intermediate 638E (7.2 mg, 0.023 mmol) and phosgene solution (15% intoluene, 0.114 mmol) were dissolved in THF (228 μL). After 1.5 hours,the reaction mixture was concentrated in vacuo to give Intermediate638F, which was used directly in the subsequent reaction.

Intermediate 638G:2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)ethyl(5-cyanopyridin-3-yl)carbamate

Intermediate 638F (8.6 mg, 0.023 mmol), 5-aminonicotinonitrile (9.48 mg,0.080 mmol), and pyridine (18.4 μl, 0.227 mmol) were dissolved in DCM(455 μL). After 45 minutes, the reaction mixture was concentrated invacuo to give Intermediate 638G, which was used directly in thesubsequent reaction: LC-MS: Method H, RT=1.07 min, MS (ESI) m/z: 461.1(M+H)⁺.

Example 638

Intermediate I-9 (8.21 mg, 0.027 mmol) and Intermediate 638G (10.5 mg,0.023 mmol) were dissolved in DMF (228 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(1.12 mg, 1.37 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 13.7 μL, 0.027 mmol)was added and the reaction degassed for 5 minutes, then sealed andheated to 100° C. in the microwave for 30 minutes. The crude materialwas purified by preparative HPLC (Method D, 65-100% B in 20 minutes) togive Example 638 (2.0 mg, 0.0033 mmol, 15%): ¹H NMR (500 MHz, DMSO-d₆) δ8.79 (br. s., 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 8.23 (br.s., 1H), 7.89 (s, 1H), 7.75 (s, 1H), 7.58 (br. s., 1H), 7.09 (br. s.,1H), 5.35 (d, J=4.9 Hz, 1H), 5.24 (d, J=4.6 Hz, 1H), 4.49 (br. s., 2H),4.30 (d, J=11.3 Hz, 2H), 4.01 (s, 3H), 2.58 (s, 3H), 0.88 (s, 9H);LC-MS: Method H, RT=1.27 min, MS (ESI) m/z: 599.2 (M+H)⁺; AnalyticalHPLC Method B, 100% purity.

Example 6398-(4-(1-hydroxy-2,2-dimethylpropyl)-6-methoxybenzo[d]thiazol-2-yl)-3-methoxyquinoxaline-6-carbonitrile

Intermediate I-38 (4.16 mg, 0.018 mmol) and Intermediate 637A (5 mg,0.015 mmol) were dissolved in DMF (151 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(0.742 mg, 0.908 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 9.08 μL, 0.018 mmol)was added and the reaction degassed for 5 minutes, then sealed andheated to 100° C. in the microwave for 30 minutes. The crude materialwas purified by preparative HPLC (Method D, 45-90% B in 20 minutes) togive Example 639 (2.1 mg, 0.0046 mmol, 30%): ¹H NMR (500 MHz, DMSO-d₆) δ9.02 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H), 7.69 (br. s., 1H), 7.23 (br.s., 1H), 5.49 (br. s., 1H), 5.38 (d, J=4.0 Hz, 1H), 4.19 (s, 3H), 3.94(s, 3H), 1.02 (s, 9H); LC-MS: Method H, RT=1.25 min, MS (ESI) m/z: 435.2(M+H)⁺; Analytical HPLC Method B, 95% purity.

Example 6401-(6-ethoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 640A:1-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one

Copper(II) chloride (0.363 g, 2.70 mmol) and t-butyl nitrite (0.344 mL,2.89 mmol) were dissolved in MeCN (7.72 mL) and allowed to stir 10minutes. Intermediate 638A (0.51 g, 1.93 mmol) was dissolved in MeCN(11.6 mL) and the copper solution was added and the reaction mixture washeated to 60° C. After 2 hours, the reaction mixture was diluted withEtOAc, washed with 1 N HCl, saturated NaHCO₃, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 40 g silica gel column, 17minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate640A (211 mg, 0.743 mmol, 39%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ7.23 (d, J=2.6 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 3.87 (s, 3H), 1.30 (s,9H); LC-MS: Method H, RT=1.15 min, MS (ESI) m/z: 284.2 (M+H)⁺.

Intermediate 640B:1-(2-chloro-6-hydroxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one

Intermediate 640A (190 mg, 0.670 mmol) and borontribromide (1 M in THF,2.01 mL, 2.01 mmol) were dissolved in DCM (6.7 mL). After 2 hours, thereaction mixture was diluted with DCM, washed with 1 N HCl, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate640B, which was used directly in the subsequent step: LC-MS: Method H,RT=1.01 min, MS (ESI) m/z: 270.1 (M+H)⁺.

Intermediate 640C:1-(2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-hydroxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one

Intermediate I-1 (221 mg, 0.872 mmol) and Intermediate 640B (196 mg,0.727 mmol) were dissolved in DMF (7.27 mL). PdCl₂(dppf)-CH₂Cl₂ adduct(35.6 mg, 0.044 mmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2M, 436 μL, 0.872 mmol) wasadded and the reaction mixture was degassed for 5 minutes, then sealedand heated to 100° C. in the microwave for 40 minutes. MorePdCl₂(dppf)-CH₂Cl₂Adduct (35.6 mg, 0.044 mmol) was added and thereaction mixture was heated for an additional 30 minutes in themicrowave at 100° C. The reaction mixture was diluted with water andextracted thrice with EtOAc. The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 40 g silicagel column, 19 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 640C (182 mg, 0.411 mmol, 57%) as a yellow solid: ¹H NMR(400 MHz, CDCl₃) δ 8.68 (d, J=1.8 Hz, 1H), 8.66 (s, 1H), 7.77 (dd,J=1.8, 0.9 Hz, 1H), 7.85-7.44 (m, 1H), 7.38 (d, J=2.4 Hz, 1H), 6.84 (d,J=2.6 Hz, 1H), 5.18 (s, 1H), 2.66 (s, 3H), 1.39 (s, 9H); LC-MS: MethodH, RT=1.21 min, MS (ESI) m/z: 444.2 (M+H)⁺.

Intermediate 640D: 1-(6-hydroxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one

Intermediate 640C (180 mg, 0.406 mmol) was azeotroped with toluene andstored on HIVAC overnight. The starting material was dissolved in THF(8.12 mL). Sodium methoxide (0.5 M in MeOH, 554 μL, 2.03 mmol) was thenadded. After 1 hour, the reaction mixture was diluted with 1 N HCl andextracted thrice with EtOAc. The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to giveIntermediate 640D (167 mg, 0.411 mmol, 100%) as an off-white solid: ¹HNMR (400 MHz, CDCl₃) δ 8.55 (d, J=1.8 Hz, 1H), 8.53 (s, 1H), 7.74 (dd,J=1.8, 0.9 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 5.08(s, 1H), 4.12 (s, 3H), 2.62 (s, 3H), 1.39 (s, 9H); LC-MS: Method H,RT=1.25 min, MS (ESI) m/z: 408.2 (M+H)⁺.

Intermediate 640E:1-(6-ethoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-one

Intermediate 640D (20 mg, 0.049 mmol) was dissolved in THF (982 μL).Cesium carbonate (16 mg, 0.049 mmol) then ethyl iodide (5.95 μL, 0.074mmol) were added. After stirring overnight, the reaction mixture wasdiluted with EtOAc, washed with water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate 640E, which wasused directly in the subsequent reaction: LC-MS: Method H, RT=1.43 min,MS (ESI) m/z: 436.2 (M+H)⁺.

Example 640

Intermediate 640E (21 mg, 0.048 mmol) was dissolved in MeOH (964 μL) andcooled to 0° C. Sodium borohydride (5.47 mg, 0.145 mmol) was then added.After 1.5 hours, the reaction was warmed to ambient temperature. After1.5 hours, the reaction mixture was diluted with EtOAc, washed withwater then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude material was purified by preparative HPLC (Method D, 60-100% Bin 30 minutes) to give Example 640 (5.7 mg, 0.013 mmol, 27%): ¹H NMR(500 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.59 (s, 1H), 7.88 (s, 1H), 7.63 (br.s., 1H), 7.19 (br. s., 1H), 5.47 (br. s., 1H), 5.38 (br. s., 1H),4.23-4.16 (m, 2H), 4.15 (s, 3H), 2.71 (s, 3H), 1.46 (t, J=6.7 Hz, 3H),1.01 (s, 9H); LC-MS: Method H, RT=1.40 min, MS (ESI) m/z: 438.2 (M+H)⁺;Analytical HPLC Method B, 100% purity.

Example 6412-(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)ethanol

Intermediate 641A: ethyl 2-(5-methoxy-2-nitrophenyl)acetate

Ethyl 2-(5-hydroxy-2-nitrophenyl)acetate (100 mg, 0.444 mmol), potassiumcarbonate (123 mg, 0.888 mmol), and iodomethane (41.6 μL, 0.666 mmol)were dissolved in acetone (4.44 mL). After stirring overnight, thereaction mixture was concentrated in vacuo, diluted with EtOAc, washedwith aqueous HCl, water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 641A (102 mg, 0.427 mmol,96%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=9.0 Hz, 1H),6.93 (dd, J=9.1, 2.8 Hz, 1H), 6.82 (d, J=2.6 Hz, 1H), 4.21 (q, J=7.1 Hz,2H), 4.02 (s, 2H), 3.92 (s, 3H), 1.29 (t, J=7.0 Hz, 3H); LC-MS: MethodH, RT=0.93 min, MS (ESI) m/z: 240.0 (M+H)⁺.

Intermediate 641B: 2-(5-methoxy-2-nitrophenyl)ethanol

Intermediate 641A (100 mg, 0.418 mmol) was dissolved in toluene (2.79mL) and THF (1.39 mL) and cooled to −78° C. DIBAL-H (1 M in toluene, 920μL, 0.920 mmol) was added and the reaction mixture was allowed to warmslowly to ambient temperature. After 1.5 hours, the reaction wasquenched with saturated Rochelle's salt. After stirring overnight, thereaction mixture was extracted with EtOAc, washed with water, thenbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crudematerial was purified by column chromatography (ISCO, 12 g silica gelcolumn, 17 minute gradient from 0 to 100% EtOAc in hexanes) to giveIntermediate 641B (65 mg, 0.33 mmol, 79%) as a yellow oil: ¹H NMR (400MHz, CDCl₃) δ 8.09 (d, J=9.0 Hz, 1H), 6.91-6.84 (m, 2H), 3.99 (t, J=6.3Hz, 2H), 3.91 (s, 3H), 3.25 (t, J=6.3 Hz, 2H); LC-MS: Method H, Did notionize well.

Intermediate 641C: 2-(2-amino-5-methoxyphenyl)ethanol

Intermediate 641B (65 mg, 0.330 mmol) was dissolved in EtOH (471 μL).Palladium on carbon (7.02 mg, 6.59 μmol) then ammonium formate (104 mg,1.65 mmol) were added and the reaction mixture was heated to reflux.After 1 hour, the reaction mixture was filtered through celite andconcentrated in vacuo to give Intermediate 641C (54.8 mg, 0.328 mmol,99%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H), 6.69 (s,2H), 3.94 (t, J=6.1 Hz, 2H), 3.77 (s, 3H), 2.82 (t, J=6.2 Hz, 2H);LC-MS: Method H, RT=0.51 min, MS (ESI) m/z: 168.0 (M+H)⁺.

Intermediate 641D: 2-(2-amino-6-methoxybenzo[d]thiazol-4-yl)ethanol

Intermediate 641C (55 mg, 0.329 mmol) was dissolved in MeCN (1.64 mL).Ammonium thiocyanate (37.6 mg, 0.493 mmol) was added, followed bybenzyltrimethylammonium tribromide (128 mg, 0.329 mmol). After stirringfor 5 days, the reaction mixture was diluted with saturated NaHCO₃. Thereaction mixture was extracted thrice with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 641D (59.9 mg, 0.267 mmol,81%) as a brown solid: LC-MS: Method H, RT=0.59 min, MS (ESI) m/z: 225.0(M+H)⁺.

Intermediate 641E: 2-(2-chloro-6-methoxybenzo[d]thiazol-4-yl)ethanol

Copper(II) chloride (50.4 mg, 0.375 mmol) and t-butyl nitrite (47.7 μL,0.401 mmol) were dissolved in MeCN (1.07 mL) and allowed to stir 10minutes. Intermediate 641D (60 mg, 0.268 mmol) was dissolved in MeCN(1.6 mL) and the copper solution was added and the reaction mixture washeated to 60° C. After 1.5 hours, the reaction mixture was diluted withEtOAc, washed with 1 N HCl, saturated NaHCO₃, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate 641E(51.6 mg, 0.212 mmol, 79%) as a red oil: ¹H NMR (400 MHz, CDCl₃) δ 7.14(d, J=2.4 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 4.02 (br. s., 2H), 3.88 (s,3H), 3.29 (t, J=6.1 Hz, 2H), 2.34 (br. s., 1H); LC-MS: Method H, RT=0.90min, MS (ESI) m/z: 244.0 (M+H)⁺.

Example 641

Intermediate I-9 (14.8 mg, 0.049 mmol) and Intermediate 641E (10 mg,0.041 mmol) were dissolved in DMF (410 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(2.01 mg, 2.46 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 24.6 μL, 0.049 mmol)was added and the reaction degassed for 5 minutes, then sealed andheated to 100° C. in the microwave for 30 minutes. The crude materialwas purified by preparative HPLC (Method D, 40-90% B in 15 minutes) togive Example 641 (6.4 mg, 0.016 mmol, 40%): ¹H NMR (500 MHz, DMSO-d₆) δ8.69 (s, 1H), 8.53 (s, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.00 (s, 1H),4.81 (t, J=5.2 Hz, 1H), 4.06 (s, 3H), 3.88-3.73 (m, 5H), 3.30 (t, J=7.0Hz, 2H), 2.62 (s, 3H); LC-MS: Method H, RT=1.19 min, MS (ESI) m/z: 382.1(M+H)⁺; Analytical HPLC Method B, 97% purity.

Example 642(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(3-(trifluoromethyl)phenyl)methanol

Intermediate 642A:(2-amino-6-methoxybenzo[d]thiazol-4-yl)(3-(trifluoromethyl)phenyl)methanol

Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1.93 mL).Sodium hydride (17 mg, 0.425 mmol) was added. After 30 minutes, thereaction mixture was cooled to −78° C. and BuLi (2.5 M in hexanes, 101μL, 0.232 mmol) was added. After 30 minutes,3-(trifluromethyl)benzaldehyde (50.4 mg, 0.289 mmol) was added and thereaction mixture was allowed to warm to ambient temperature. Afterachieving ambient temperature, the reaction mixture was diluted withEtOAc, washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 642A, which was used directlyin the subsequent reaction: LC-MS: Method H, RT=0.83 min, MS (ESI) m/z:355.0 (M+H)⁺.

Intermediate 642B:(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(3-(trifluoromethyl)phenyl)methanol

Intermediate 642A (68 mg, 0.192 mmol), lithium chloride (8.14 mg, 0.192mmol), copper(II) chloride (25.8 mg, 0.192 mmol), and tert-butyl nitrite(22.9 μL, 0.192 mmol) were dissolved in MeCN (1.92 mL). After 2 hours,the reaction mixture was diluted with EtOAc, washed with 1 N HCl,saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to give Intermediate 642B (73.5 mg, 0.197 mmol, 100%) as a redoil: LC-MS: Method H, RT=1.10 min, MS (ESI) m/z: 374.0 (M+H)⁺.

Example 642

Intermediate I-9 (15 mg, 0.050 mmol) and Intermediate 642B (22.4 mg,0.060 mmol) were dissolved in DMF (250 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(2.45 mg, 3.00 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 30.0 μL, 0.060 mmol)was added and the reaction degassed for 5 minutes, then sealed andheated to 100° C. in the microwave for 30 minutes. The crude materialwas purified by preparative HPLC (Method D, 45-90% B in 20 minutes) thenrepurified by preparative HPLC (Method D, 60-100% B in 15 minutes) togive Example 642 (7.5 mg, 0.015 mmol, 29%): ¹H NMR (500 MHz, DMSO-d₆) δ8.78 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.87 (d, J=7.6Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.64-7.55 (m, 2H), 7.41 (d, J=2.1 Hz,1H), 6.76 (d, J=4.3 Hz, 1H), 6.44 (d, J=4.3 Hz, 1H), 4.14 (s, 3H), 3.94(s, 3H), 2.72 (s, 3H); LC-MS: Method H, RT=1.34 min, MS (ESI) m/z: 512.1(M+H)⁺; Analytical HPLC Method B, 100% purity.

Example 643(2-isopropylphenyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol

Intermediate 643A:(2-amino-6-methoxybenzo[d]thiazol-4-yl)(2-isopropylphenyl)methanol

Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1.93 mL).Sodium hydride (17 mg, 0.425 mmol) was then added. After 30 minutes, thereaction mixture was cooled to −78° C. and BuLi (2.5 M in hexanes, 101μL, 0.232 mmol) was added. After 30 minutes, 2-isopropylbenzaldehyde(42.9 mg, 0.289 mmol) was added and the reaction mixture was allowed towarm to ambient temperature. After achieving ambient temperature, thereaction mixture was diluted with EtOAc, washed with water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate643A, which was used directly in the subsequent reaction: LC-MS: MethodH, RT=0.87 min, MS (ESI) m/z: 329.1 (M+H)⁺.

Intermediate 643B:(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(2-isopropylphenyl)methanol

Intermediate 643A (63 mg, 0.192 mmol), lithium chloride (8.13 mg, 0.192mmol), copper(II) chloride (25.8 mg, 0.192 mmol), and tert-butyl nitrite(22.9 μL, 0.192 mmol) were dissolved in MeCN (1.92 mL). After 2 hours,the reaction mixture was diluted with EtOAc, washed with 1 N HCl,saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to give Intermediate 643B, which was used directly in thesubsequent reaction: LC-MS: Method H, RT=1.18 min, MS (ESI) m/z: 348(M+H)⁺.

Example 643

Intermediate I-9 (15 mg, 0.050 mmol) and Intermediate 643B (20.9 mg,0.060 mmol) were dissolved in DMF (250 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(2.45 mg, 3.00 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 30.0 μL, 0.060 mmol)was added and the reaction degassed for 5 minutes, then sealed andheated to 100° C. in the microwave for 30 minutes. The crude materialwas purified by preparative HPLC (Method D, 50-100% B in 20 minutes)then repurified by preparative HPLC (Method D, 60-100% B in 20 minutes)to give Example 643 (1.7 mg, 0.0034 mmol, 6.7%): ¹H NMR (500 MHz,DMSO-d₆) δ 8.71 (s, 1H), 8.45 (s, 1H), 7.80 (s, 1H), 7.61 (d, J=2.4 Hz,1H), 7.36-7.26 (m, 3H), 7.20 (t, J=7.6 Hz, 1H), 7.14-7.08 (m, 1H), 6.98(d, J=4.9 Hz, 1H), 5.92 (d, J=5.2 Hz, 1H), 4.07 (s, 3H), 3.96-3.85 (m,4H), 2.60 (s, 3H), 1.32 (d, J=7.0 Hz, 3H), 1.21 (d, J=6.7 Hz, 3H);LC-MS: Method H, RT=1.37 min, MS (ESI) m/z: 486.1 (M+H)⁺; AnalyticalHPLC Method B, 96% purity.

Example 644 Ethyl1-(hydroxy(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methyl)cyclobutanecarboxylate

Intermediate 644A: Ethyl1-(2-amino-6-methoxybenzo[d]thiazole-4-carbonyl)cyclobutanecarboxylate

Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1.93 mL).Sodium hydride (17 mg, 0.425 mmol) was then added. After 15 minutes, thereaction mixture was cooled to −78° C. and BuLi (2.5 M in hexanes, 101μL, 0.232 mmol) was added. After 30 minutes, diethylcyclobutane-1,1-dicarboxylate (58.0 mg, 0.289 mmol) was added and thereaction mixture was allowed to warm to ambient temperature. Afterachieving ambient temperature, the reaction mixture was diluted withEtOAc, washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 644A, which was used directlyin the subsequent reaction: LC-MS: Method H, RT=0.77 min, MS (ESI) m/z:335.0 (M+H)⁺.

Intermediate 644B: Ethyl1-(2-chloro-6-methoxybenzo[d]thiazole-4-carbonyl)cyclobutane-1-carboxylate

Intermediate 644A (64.5 mg, 0.193 mmol), lithium chloride (8.18 mg,0.193 mmol), copper(II) chloride (25.9 mg, 0.193 mmol), and tert-butylnitrite (23 μL, 0.193 mmol) were dissolved in MeCN (1.93 mL). After 2hours, the reaction mixture was diluted with EtOAc, washed with 1 N HCl,saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The crude material was purified by column chromatography(ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAcin hexanes) to give Intermediate 644B (12 mg, 0.034 mmol, 18%) as awhite solid: LC-MS: Method H, RT=1.16 min, MS (ESI) m/z: 354.1 (M+H)⁺.

Intermediate 644C: Ethyl1-((2-chloro-6-methoxybenzo[d]thiazol-4-yl)(hydroxy)methyl)cyclobutane-1-carboxylate

Intermediate 644B (12 mg, 0.034 mmol) was dissolved in MeOH (339 μL) at0° C. Sodium borohydride (2.57 mg, 0.068 mmol). After 45 minutes, thereaction mixture was diluted with EtOAc, washed with water then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate644C, which was used directly in the subsequent reaction: LC-MS: MethodH, RT=1.07 min, MS (ESI) m/z: 356.0 (M+H)⁺.

Example 644

Intermediate I-9 (12.2 mg, 0.040 mmol) and Intermediate 644C (12 mg,0.034 mmol) were dissolved in DMF (169 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(1.65 mg, 2.02 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes.

Sodium carbonate (20.2 μL, 0.040 mmol) was added and the reactiondegassed for 5 minutes, then sealed and heated to 100° C. in themicrowave for 30 minutes. The crude material was purified by preparativeHPLC (Method D, 60-100% B in 22 minutes) to give Example 644 (3.1 mg,0.0062 mmol, 18%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.47 (s,1H), 7.75 (s, 1H), 7.55 (s, 1H), 7.08 (d, J=1.7 Hz, 1H), 5.83 (d, J=5.4Hz, 1H), 5.78 (d, J=5.7 Hz, 1H), 4.01 (s, 3H), 3.88-3.78 (m, 3H), 3.76(dd, J=7.1, 4.4 Hz, 2H), 2.57 (s, 3H), 2.53-2.35 (m, 2H), 2.19 (br. s.,1H), 2.08 (br. s., 1H), 1.67-1.58 (m, 1H), 1.54 (br. s., 1H), 0.87 (t,J=7.1 Hz, 3H); LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 494.1 (M+H)⁺;Analytical HPLC Method B, 99% purity.

Example 645(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-121 (12 mg, 0.038 mmol), Intermediate I-130 (18.5 mg,0.045 mmol) and PdCl₂(dppf) (1.65 mg, 2.25 μmol) were dissolved in1,4-dioxane (375 μL) and Na₂CO₃ (2 M, 169 μL, 0.338 mmol) and heated to100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature, diluted with EtOAc, washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by preparative HPLC (Method D, 50-100% B in 20 minutes) to giveExample 645 (6.6 mg, 0.011 mmol, 30%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.92(br. s., 1H), 8.82 (br. s., 1H), 8.71 (br. s., 2H), 8.58 (s, 1H), 8.15(s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.93 (d, J=11.9 Hz, 1H), 7.90 (br. s.,1H), 5.11 (d, J=6.1 Hz, 1H), 4.82 (d, J=6.1 Hz, 1H), 3.98 (s, 3H), 2.50(s, 3H), 1.39 (t, J=6.7 Hz, 6H); LC-MS: Method H, RT=1.21 min, MS (ESI)m/z: 568.1 (M+H)⁺; Analytical HPLC Method B, 96% purity.

Example 646(1-(hydroxymethyl)cyclobutyl)(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)methanol

Intermediate 646A: Methyl1-(2-amino-6-methoxybenzo[d]thiazole-4-carbonyl)cyclobutanecarboxylate

Intermediate I-22 (1 g, 3.86 mmol) was dissolved in THF (38.6 mL).Sodium hydride (0.340 g, 8.49 mmol) was then added. After 15 minutes,the reaction mixture was cooled to −78° C. and BuLi (2.5 M in hexanes,2.01 mL, 4.63 mmol) was added. After 45 minutes, dimethylcyclobutane-1,1-dicarboxylate (0.892 mL, 5.79 mmol) was added and thereaction mixture was allowed to warm to ambient temperature. After thereaction reached ambient temperature, it was diluted with EtOAc, washedwith water, then brine, dried (Na₂SO₄), filtered, and concentrated invacuo to give Intermediate 646A, which was used directly in thesubsequent step: LC-MS: Method H, RT=0.75 min, MS (ESI) m/z: 321.1(M+H)⁺.

Intermediate 646B: Methyl1-(2-chloro-6-methoxybenzo[d]thiazole-4-carbonyl)cyclobutanecarboxylate

Intermediate 646A (1.24 g, 3.86 mmol), lithium chloride (0.164 g, 3.86mmol), copper(II) chloride (0.519 g, 3.86 mmol), and tert-butyl nitrite(0.460 mL, 3.86 mmol) were dissolved in MeCN (38.6 mL). After 2 hours,the reaction mixture was diluted with EtOAc, washed with 1 N HCl,saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The crude material was purified by column chromatography(ISCO, 12 g silica gel column, 17 minute gradient from 0 to 100% EtOAcin hexanes) to give Intermediate 646B (124 mg, 0.365 mmol, 9.5% over 2steps) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=2.6 Hz,1H), 7.43 (d, J=2.6 Hz, 1H), 3.92 (s, 3H), 3.68 (s, 3H), 2.80-2.65 (m,2H), 2.64-2.50 (m, 2H), 2.25-2.11 (m, 1H), 1.94-1.80 (m, 1H); LC-MS:Method H, RT=1.14 min, MS (ESI) m/z: 340.1 (M+H)⁺.

Intermediate 646C:(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(hydroxymethyl)cyclobutyl)methanol

Intermediate 646B (124 mg, 0.365 mmol) and NaBH₄ (13.8 mg, 0.365 mmol)were dissolved in MeOH (1.82 mL) at 0° C. After 4 hours, the reactionmixture was diluted with EtOAc, washed with water then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 12 g silica gel column, 17minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate646C (23.8 mg, 0.076 mmol, 21%) as a clear oil: ¹H NMR (500 MHz, CDCl₃)δ 7.19 (d, J=2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 5.41 (d, J=5.8 Hz,1H), 3.88 (s, 3H), 3.74-3.67 (m, 1H), 3.46-3.36 (m, 2H), 3.26 (d, J=5.8Hz, 1H), 2.38-2.22 (m, 2H), 1.89 (dd, J=9.2, 3.2 Hz, 1H), 1.82-1.72 (m,2H), 1.53-1.49 (m, 1H); LC-MS: Method H, RT=0.95 min, MS (ESI) m/z:314.1 (M+H)⁺.

Example 646

Intermediate I-9 (20.1 mg, 0.067 mmol) and Intermediate 646C (20 mg,0.064 mmol) were dissolved in DMF (319 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(3.12 mg, 3.82 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Sodium carbonate (2 M, 38.2 μL, 0.076 mmol)was added and the reaction degassed for 5 minutes, then sealed andheated to 100° C. in the microwave for 30 minutes. MorePdCl₂(dppf)-CH₂Cl₂ adduct (3.12 mg, 3.82 μmol) was added and thereaction mixture was heated in the microwave for an additional 30minutes at 100° C. The crude material was purified by preparative HPLC(Method D, 45-95% B in 20 minutes) to give Example 646 (12.4 mg, 0.026mmol, 41%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.47 (br. s., 1H),7.82 (br. s., 1H), 7.60 (br. s., 1H), 7.20 (br. s., 1H), 5.64 (br. s.,1H), 5.51 (br. s., 1H), 4.80 (br. s., 1H), 4.08 (s, 3H), 3.47 (br. s.,1H), 3.26 (d, J=5.5 Hz, 1H), 2.63 (br. s., 3H), 2.35 (br. s., 1H), 2.17(br. s., 1H), 1.79-1.55 (m, 4H); LC-MS: Method H, RT=1.22 min, MS (ESI)m/z: 452.1 (M+H)⁺; Analytical HPLC Method B, 96% purity.

Example 647 (2R,3S)-3-((2-(6-chloro-3-ethylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate 647A: 8-bromo-6-chloro-3-ethylquinoline

Intermediate I-123 (185 mg, 0.789 mmol), butyraldehyde (71.1 μL, 0.789mmol), and sodium methoxide (0.5 M in MeOH, 1.74 mL, 0.868 mmol) weredissolved in MeOH (1.58 mL) and heated to reflux. After heatingovernight, the reaction mixture was diluted with saturated NH₄Cl,partially concentrated in vacuo and diluted with EtOAc. The layers wereseparated and the organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 24 g silica gel column, 19 minute gradientfrom 0 to 50% EtOAc in hexanes) to give Intermediate 647A (192 mg, 0.710mmol, 90%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J=2.2Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 7.87-7.82 (m, 1H), 7.74 (d, J=2.2 Hz,1H), 2.88 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.6 Hz, 3H); LC-MS: Method H,RT=1.20 min, MS (ESI) m/z: 270/272 (M+H)⁺.

Intermediate 647B:6-chloro-3-ethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate 647A (192 mg, 0.710 mmol), bispinacolatodiboron (216 mg,0.852 mmol), and potassium acetate (174 mg, 1.78 mmol) were dissolved in1,4-dioxane (7.1 mL) and degassed for 5 minutes by bubbling with argon.PdCl₂(dppf)-CH₂Cl₂ adduct (46.4 mg, 0.057 mmol) was added and thereaction degassed for an additional 10 minutes. The reaction mixture washeated to 130° C. in the microwave for 2 hours. The reaction mixture wasdiluted with EtOAc and water. The reaction was further extracted twicewith EtOAc. The combined organic layers were washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate 647B,which was used directly in the subsequent reaction: LC-MS: Method H,RT=0.93 min, MS (ESI) m/z: 236.1 (boronic acid mass observed, M+H)⁺.

Example 647

Intermediate 647B (15 mg, 0.047 mmol), I-130 (19.4 mg, 0.047 mmol) andPdCl₂(dppf) (2.07 mg, 2.83 μmol) were dissolved in 1,4-dioxane (472 μL)and Na₂CO₃ (2 M, 213 μL, 0.425 mmol) and heated to 100° C. After 1 hour,the reaction mixture was cooled to ambient temperature, diluted withEtOAc, washed with water, then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by preparativeHPLC (Method D, 65-100% B in 25 minutes) to give Example 647 (4.3 mg,0.0074 mmol, 15%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.93 (br. s., 1H), 9.06(d, J=2.1 Hz, 1H), 8.77 (d, J=2.1 Hz, 1H), 8.73 (br. s., 2H), 8.34 (s,1H), 8.28 (d, J=2.4 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.99 (d, J=11.6 Hz,1H), 5.11 (dd, J=6.6, 2.6 Hz, 1H), 4.84 (dd, J=6.4, 2.7 Hz, 1H), 2.92(q, J=7.4 Hz, 2H), 2.55 (s, 3H), 1.40 (dd, J=6.3, 4.4 Hz, 6H), 1.35 (t,J=7.6 Hz, 3H); LC-MS: Method H, RT=1.30 min, MS (ESI) m/z: 566.1 (M+H)⁺;Analytical HPLC Method B, 98% purity.

Example 648(2R,3S)-3-((5-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-124 (15 mg, 0.050 mmol), Intermediate I-130 (20.6 mg,0.050 mmol) and PdCl₂(dppf) (2.2 mg, 3.01 μmol) were dissolved in1,4-dioxane (501 μL) and Na₂CO₃ (2 M, 226 μL, 0.451 mmol) and heated to100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature and concentrated in vacuo. The crude material was purifiedby preparative HPLC (Method D, 45-100% B in 15 minutes) to give Example648 (8.4 mg, 0.015 mmol, 30%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br. s.,1H), 8.79 (d, J=2.7 Hz, 1H), 8.74 (br. s., 2H), 8.61 (d, J=1.5 Hz, 1H),8.03 (d, J=8.2 Hz, 1H), 7.94 (d, J=11.6 Hz, 1H), 7.89-7.82 (m, 2H),5.16-5.05 (m, 1H), 4.80 (dd, J=6.1, 2.7 Hz, 1H), 3.99 (s, 3H), 2.61 (s,3H), 1.40 (dd, J=6.4, 2.4 Hz, 6H) (1 methyl group under solvent); LC-MS:Method H, RT=1.14 min, MS (ESI) m/z: 548.1 (M+H)⁺; Analytical HPLCMethod B, 99% purity.

Example 649(2R,3S)-3-((2-(6-chloro-3-ethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-126 (15 mg, 0.045 mmol), Intermediate I-130 (18.5 mg,0.045 mmol) and PdCl₂(dppf) (1.97 mg, 2.70 μmol) were dissolved in1,4-dioxane (450 μL) and Na₂CO₃ (2 M, 202 μL, 0.405 mmol) and heated to100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature. The reaction mixture was concentrated in vacuo. The crudematerial was purified by preparative HPLC (Method D, 50-100% B in 20minutes) then repurified by preparative HPLC (Method D, 50-100% B in 20minutes) to give Example 649 (2.5 mg, 0.0041 mmol, 9.2%): ¹H NMR (500MHz, DMSO-d₆) δ 9.94 (br. s., 1H), 8.85 (d, J=2.7 Hz, 1H), 8.73 (br. s.,2H), 8.62 (d, J=2.1 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.05 (d, J=8.2 Hz,1H), 7.97 (d, J=11.6 Hz, 1H), 7.93 (d, J=2.7 Hz, 1H), 5.11 (dd, J=6.6,2.6 Hz, 1H), 4.82 (dd, J=6.4, 2.4 Hz, 1H), 4.27 (q, J=7.0 Hz, 2H), 2.55(s, 3H), 1.46 (t, J=6.9 Hz, 3H), 1.40 (t, J=5.5 Hz, 6H); LC-MS: MethodH, RT=1.30 min, MS (ESI) m/z: 582.1 (M+H)⁺; Analytical HPLC Method B,96% purity.

Example 650(2R,3S)-3-((2-(6-chloro-3-(difluoromethoxy)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-127 (22 mg, 0.062 mmol), Intermediate I-130 (25.4 mg,0.062 mmol) and PdCl₂(dppf) (2.72 mg, 3.71 μmol) were dissolved in1,4-dioxane (619 μL) and Na₂CO₃ (2 M, 278 μL, 0.557 mmol) and heated to100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature and concentrated in vacuo. The crude material was purifiedby preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example650 (3.9 mg, 0.0063 mmol, 10%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.93 (br.s., 1H), 9.06 (d, J=2.4 Hz, 1H), 8.78 (s, 1H), 8.72 (br. s., 2H), 8.36(br. s., 2H), 8.07 (d, J=7.9 Hz, 1H), 7.99 (d, J=11.3 Hz, 1H), 7.67-7.34(m, 1H), 5.11 (dd, J=6.4, 2.1 Hz, 1H), 4.88-4.79 (m, 1H), 2.55 (s, 3H),1.40 (t, J=5.8 Hz, 6H); LC-MS: Method H, RT=1.37 min, MS (ESI) m/z:604.1 (M+H)⁺; Analytical HPLC Method B, 98% purity.

Example 651(2R,3S)-3-((2-(6-chloro-3-(2,2-difluoroethoxy)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate 651A: 8-bromo-6-chloro-3-(2,2-difluoroethoxy)quinoline

Intermediate I-122 (82 mg, 0.317 mmol), K₂CO₃ (132 mg, 0.952 mmol), and2-bromo-1,1-difluoroethane (92 mg, 0.634 mmol) were dissolved in Acetone(3.17 mL) and heated to 50° C. in a sealed tube. After heatingovernight, the reaction mixture was diluted with EtOAc, washed withwater, then brine, dried (Na₂SO₄), filtered, and concentrated in vacuoto give Intermediate 651A (60.4 mg, 0.187 mmol, 59%) as an orange solid:¹H NMR (400 MHz, CDCl₃) δ 8.80 (d, J=2.9 Hz, 1H), 7.91 (d, J=2.2 Hz,1H), 7.71 (d, J=2.2 Hz, 1H), 7.33 (d, J=2.9 Hz, 1H), 6.36-6.02 (m, 1H),4.34 (td, J=12.8, 4.0 Hz, 2H); LC-MS: Method H, RT=1.19 min, MS (ESI)m/z: 322/324 (M+H)⁺.

Intermediate 651B:6-chloro-3-(2,2-difluoroethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate 651A (60.4 mg, 0.187 mmol), bispinacolatodiboron (57.1 mg,0.225 mmol), and potassium acetate (45.9 mg, 0.468 mmol) were dissolvedin 1,4-dioxane (1.87 mL) and degassed for 5 minutes by bubbling withargon. PdCl₂(dppf)-CH₂Cl₂ adduct (12.2 mg, 0.015 mmol) was added and thereaction degassed for an additional 10 minutes. The reaction mixture washeated to 130° C. in the microwave for 2 hours. The reaction mixture wasdiluted with EtOAc and water. The reaction was further extracted twicewith EtOAc. The combined organic layers were washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate 651B,which was used directly in the subsequent reaction: LC-MS: Method H,RT=1.14 min, MS (ESI) m/z: 287.9 (M+H)⁺.

Example 651

Intermediate 651B (17 mg, 0.046 mmol), Intermediate I-130 (18.9 mg,0.046 mmol) and PdCl₂(dppf) (2.02 mg, 2.76 μmol) were dissolved in1,4-dioxane (460 μL) and Na₂CO₃ (2 M, 207 μL, 0.414 mmol) and heated to100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature and concentrated in vacuo. The crude material was purifiedby preparative HPLC (Method D, 50-100% B in 20 minutes) then repurifiedby preparative HPLC (Method D, 45-90% in 20 minutes) to give Example 651(3.6 mg, 0.0058 mmol, 13%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.94 (br. s.,1H), 8.95 (br. s., 1H), 8.73 (br. s., 2H), 8.67 (s, 1H), 8.18 (s, 1H),8.11-8.03 (m, 2H), 7.98 (d, J=11.3 Hz, 1H), 6.67-6.42 (m, 1H), 5.11 (d,J=6.4 Hz, 1H), 4.82 (d, J=6.1 Hz, 1H), 4.60 (t, J=13.6 Hz, 2H), 2.55 (s,3H), 1.40 (t, J=5.3 Hz, 6H); LC-MS: Method H, RT=1.37 min, MS (ESI) m/z:604.1 (M+H)⁺; Analytical HPLC Method B, 100% purity.

Example 652(2R,3S)-3-((2-(6-chloro-3-(methylamino)quinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate 652A: tert-butyl(8-bromo-6-chloroquinolin-3-yl)(methyl)carbamate

Intermediate I-123 (100 mg, 0.426 mmol), tert-butyl methyl(2-oxoethyl)carbamate (73.9 mg, 0.426 mmol), and sodium methoxide (0.5 M in MeOH,938 μL, 0.469 mmol) were dissolved in MeOH (1.71 mL) and heated toreflux. After heating overnight, the reaction mixture was diluted withsaturated NH₄Cl, partially concentrated in vacuo and diluted with EtOAc.The layers were separated and the organic layer was washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude materialwas purified by column chromatography (ISCO, 24 g silica gel column, 21minute gradient from 0 to 50% EtOAc in hexanes) to give Intermediate652A (64 mg, 0.172 mmol, 40%) as an orange oil: ¹H NMR (500 MHz, CDCl₃)δ 9.02 (d, J=2.5 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.90 (d, J=2.2 Hz,1H), 7.76 (d, J=2.2 Hz, 1H), 3.42 (s, 3H), 1.51 (s, 9H); LC-MS: MethodH, RT=1.39 min, MS (ESI) m/z: 371/373 (M+H)⁺.

Intermediate 652B: 8-bromo-6-chloro-N-methylquinolin-3-amine

Intermediate 652A (64 mg, 0.172 mmol) was dissolved in DCM (1.72 mL) andTFA (66.3 μL, 0.861 mmol). After stirring for 4 days, the reactionmixture was diluted with DCM, washed with 1N NaOH, water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate652B (43.4 mg, 0.160 mmol, 93%) as an off-white solid: ¹H NMR (400 MHz,CDCl₃) δ 8.49 (d, J=2.9 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.58 (d, J=2.0Hz, 1H), 6.85 (d, J=2.9 Hz, 1H), 4.27 (br. s., 1H), 2.96 (d, J=5.1 Hz,3H); LC-MS: Method H, RT=1.31 min, MS (ESI) m/z: 271/273 (M+H)⁺.

Intermediate 652C:6-chloro-N-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-amine

Intermediate 652B (20 mg, 0.074 mmol), bispinacolatodiboron (37.4 mg,0.147 mmol), potassium acetate (18.1 mg, 0.184 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (4.81 mg, 5.89 μmol) were stored on HIVAC for15 minutes then were dissolved in dry 1,4-dioxane (368 μL) and degassedfor 15 minutes by bubbling with argon. The reaction mixture was heatedto 130° C. in the microwave for 40 minutes. The reaction mixture wasdiluted with EtOAc and washed with water then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate 652C, which wasused directly in the subsequent reaction: LC-MS: Method H, RT=0.98 min,MS (ESI) m/z: 237.0 (boronic acid mass observed, M+H)⁺.

Example 652

Intermediate 652C (8 mg, 0.025 mmol), Intermediate I-130 (10.3 mg, 0.025mmol) and PdCl₂(dppf) (1.1 mg, 1.51 μmol) were dissolved in 1,4-dioxane(251 μL) and Na₂CO₃ (2 M, 113 μL, 0.226 mmol) and heated to 100° C.After 1 hour, the reaction mixture was cooled to ambient temperature andconcentrated in vacuo. The crude material was purified by preparativeHPLC (Method D, 40-80% in 20 minutes) to give Example 652 (3.3 mg,0.0057 mmol, 23%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.94 (br. s., 1H), 8.73(br. s., 2H), 8.67 (br. s., 1H), 8.39 (s, 1H), 8.03 (d, J=7.6 Hz, 1H),7.99-7.91 (m, 2H), 7.64-7.48 (m, 1H), 7.14 (br. s., 1H), 5.11 (d, J=6.1Hz, 1H), 4.81 (d, J=6.1 Hz, 1H), 2.85 (br. s., 3H), 2.55 (s, 3H), 1.40(d, J=6.1 Hz, 6H); LC-MS: Method H, compound did not ionize; AnalyticalHPLC Method B, 98% purity.

Example 653(2R,3S)-3-((2-(6-(difluoromethyl)-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-128 (15 mg, 0.045 mmol), Intermediate I-130 (18.4 mg,0.045 mmol) and PdCl₂(dppf) (1.96 mg, 2.69 μmol) were dissolved in1,4-dioxane (448 μL) and Na₂CO₃ (2 M, 201 μL, 0.403 mmol) and heated to100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature and concentrated in vacuo. The crude material was purifiedby preparative HPLC (Method D, 45-90% B in 22 minutes) to give Example653 (5.1 mg, 0.0087 mmol, 19%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.91 (br.s., 1H), 8.90 (d, J=2.4 Hz, 1H), 8.82 (s, 1H), 8.70 (br. s., 2H), 8.30(s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.95 (d, J=11.6Hz, 1H), 7.33 (t, J=44 Hz, 1H), 5.15-5.06 (m, 1H), 4.81 (d, J=4.0 Hz,1H), 3.99 (s, 3H), 2.49 (s, 3H), 1.38 (t, J=7.2 Hz, 6H); LC-MS: MethodH, RT=1.11 min, MS (ESI) m/z: 584.1 (M+H)⁺; Analytical HPLC Method B,99% purity.

Example 654(2R,3S)-3-((5-fluoro-2-(6-(fluoromethyl)-3-methoxyquinolin-8-yl)benzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-129 (15 mg, 0.047 mmol), Intermediate I-130 (19.4 mg,0.047 mmol) and PdCl₂(dppf) (2.08 mg, 2.84 μmol) were dissolved in1,4-dioxane (473 μL) and Na₂CO₃ (2 M, 213 μL, 0.426 mmol) and heated to100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature and concentrated in vacuo. The crude material was purifiedby preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example654 (2.5 mg, 0.0043 mmol, 9.1%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.96 (br.s., 1H), 8.89 (d, J=2.7 Hz, 1H), 8.75 (d, J=14.0 Hz, 3H), 8.13 (s, 1H),8.07-8.00 (m, 2H), 7.96 (d, J=11.6 Hz, 1H), 5.76 (d, J=20 Hz, 2H), 5.12(dd, J=6.4, 2.7 Hz, 1H), 4.82 (d, J=3.7 Hz, 1H), 4.01 (s, 3H), 3.45 (s,3H), 1.46-1.34 (m, 6H); LC-MS: Method H, RT=1.07 min, MS (ESI) m/z:566.1 (M+H)⁺; Analytical HPLC Method B, 97% purity.

Example 655(2R,3S)-3-((2-(6-cyano-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate 655A: methyl 2-amino-3-bromo-5-cyanobenzoate

Methyl 2-amino-5-cyanobenzoate (0.25 g, 1.42 mmol) and NBS (0.253 g,1.42 mmol) were dissolved in AcOH (2.84 mL) and heated to 120° C. After2 hours, the reaction mixture was cooled to ambient temperature anddiluted with EtOAc. The reaction was then quenched with vigorousstirring with saturated NaHCO₃. The layers were separated and theorganic layer further washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give Intermediate 655A (356 mg, 1.4 mmol, 98%)as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=1.8 Hz, 1H), 7.82(d, J=1.8 Hz, 1H), 3.95 (s, 3H); LC-MS: Method H, compound did notionize

Intermediate 655B: 4-amino-3-bromo-5-(hydroxymethyl)benzonitrile

Intermediate 655A (356 mg, 1.4 mmol) was dissolved in THF (4.65 mL).Lithium borohydride (60.8 mg, 2.79 mmol) was added and the reactionmixture was heated to 50° C. After 1 hour, the reaction mixture wasdiluted with water. The reaction mixture was then extracted thrice withEtOAc. The combined organic layers were washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, dry load, 40 g silica gelcolumn, 19 minute gradient from 0 to 100% EtOAc in hexanes, polarweighted) to give Intermediate 655B (106 mg, 0.465 mmol, 33%) as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=1.8 Hz, 1H), 7.32 (d, J=1.8Hz, 1H), 5.35 (br. s., 2H), 4.73 (s, 2H), 1.79 (br. s., 1H); LC-MS:Method H, compound did not ionize

Intermediate 655C: 4-amino-3-bromo-5-formylbenzonitrile

Intermediate 655B (106 mg, 0.465 mmol) was dissolved in CHCl₃ (3.1 mL).Manganese dioxide (243 mg, 2.79 mmol) was added and the reaction mixturewas heated to 40° C. After heating overnight, the reaction mixture wasfiltered through celite and concentrated in vacuo to give Intermediate655C (88.3 mg, 0.392 mmol, 84%) as a white solid: ¹H NMR (400 MHz,CDCl₃) δ 9.85 (s, 1H), 7.88-7.86 (m, 1H), 7.86-7.83 (m, 1H); LC-MS:Method H, compound did not ionize.

Intermediate 655D: 3-(benzyloxy)-8-bromoquinoline-6-carbonitrile

Intermediate 655C (88.3 mg, 0.392 mmol), 2-(benzyloxy)acetaldehyde (58.9mg, 0.392 mmol), and sodium methoxide (0.5 M, 863 μL, 0.432 mmol) weredissolved in MeOH (1.57 mL) and heated to reflux. After heatingovernight, the reaction mixture was diluted with saturated NH₄Cl,partially concentrated in vacuo and diluted with EtOAc. The layers wereseparated and the organic layer was washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 40 g silica gel column, 19 minute gradientfrom 0 to 100% EtOAc in hexanes) to give Intermediate 655D (59.5 mg,0.175 mmol, 45%) as a yellow solid: LC-MS: Method H, RT=1.11 min, MS(ESI) m/z: 339/341 (M+H)⁺.

Intermediate 655E: 8-bromo-3-hydroxyquinoline-6-carbonitrile, HCl

Intermediate 655D (59 mg, 0.174 mmol) and pentamethylbenzene (181 mg,1.218 mmol) were dissolved in DCM (3.48 mL) and cooled to −78° C. Borontrichloride (1 M in heptane, 452 μL, 0.452 mmol) was added and thereaction mixture was allowed to slowly warm to ambient temperature.After stirring overnight, the reaction mixture was diluted with hexanesand 1 N HCl and allowed to stir for 1 hour. The solid was collected bysuction filtration to give Intermediate 655E (24.5 mg, 0.086 mmol, 49%)as a white solid: ¹H NMR (400 MHz, MeOH₄) δ 8.73 (d, J=2.9 Hz, 1H), 8.27(d, J=1.8 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.59 (d, J=2.6 Hz, 1H);LC-MS: Method H, RT=0.80 min, MS (ESI) m/z: 249/251 (M+H)⁺.

Intermediate 655F: 8-bromo-3-methoxyquinoline-6-carbonitrile

Intermediate 655E (24.5 mg, 0.086 mmol), K₂CO₃ (35.6 mg, 0.257 mmol),and methyl iodide (10.7 μL, 0.172 mmol) were dissolved in acetone (858μL) and heated to 50° C. in a sealed tube. After heating overnight, thereaction mixture was diluted with EtOAc, washed with water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate655F (21.5 mg, 0.082 mmol, 95%) as a white solid: ¹H NMR (400 MHz,CDCl₃) δ 8.92 (d, J=2.9 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 8.07 (d, J=1.5Hz, 1H), 7.43 (d, J=2.9 Hz, 1H), 4.03 (s, 3H); LC-MS: Method H, RT=0.93min, MS (ESI) m/z: 263/265 (M+H)⁺.

Intermediate 655G:3-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-6-carbonitrile

Intermediate 655F (21 mg, 0.080 mmol), bispinacolatodiboron (40.5 mg,0.160 mmol), potassium acetate (19.6 mg, 0.200 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (5.21 mg, 6.39 μmol) were stored on HIVAC for15 minutes then were dissolved in 1,4-dioxane (399 μL) and degassed for15 minutes by bubbling with argon. The reaction mixture was heated to130° C. in the microwave for 40 minutes. The reaction mixture wasdiluted with EtOAc and washed with water then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate 655G, which wasused directly in the subsequent reaction.

Example 655

Intermediate 655G (20 mg, 0.064 mmol), Intermediate I-130 (26.5 mg,0.064 mmol) and PdCl₂(dppf) (2.83 mg, 3.87 μmol) were dissolved in1,4-dioxane (645 μL) and Na₂CO₃ (2 M, 290 μL, 0.580 mmol) and heated to100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature and concentrated in vacuo. The crude material was purifiedby preparative HPLC (Method D, 45-90% B in 20 minutes) then repurifiedby preparative HPLC (Method D, 40-80% B in 20 minutes) to give Example655 (1.3 mg, 0.0023 mmol, 3.6%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br.s., 1H), 8.95 (d, J=2.4 Hz, 1H), 8.80-8.69 (m, 3H), 8.60 (s, 1H),8.05-7.98 (m, 2H), 7.93 (d, J=11.6 Hz, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.82(d, J=4.0 Hz, 1H), 4.01 (s, 3H), 3.41 (br. s., 3H), 1.41 (t, J=6.6 Hz,6H); LC-MS: Method H, compound did not ionize; Analytical HPLC Method B,100% purity.

Example 656(2-(6-chloro-3-methoxyquinolin-8-yl)-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanol

Intermediate 656A:(2-amino-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanone

Intermediate I-22 (1 g, 3.86 mmol) was dissolved in THF (38.6 mL). NaH(0.170 g, 4.25 mmol) was added. After 15 minutes, the reaction mixturewas cooled to −78° C. and BuLi (1.93 mL, 4.82 mmol) was added. After 30minutes, ethyl 1-(trifluoromethyl) cyclobutanecarboxylate (2.27 g, 11.6mmol) was added and the reaction mixture was allowed to warm to ambienttemperature. After achieving ambient temperature, the reaction mixturewas diluted with EtOAc and washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate 656A,which was used directly in the subsequent step: LC-MS: Method H, RT=0.79min, MS (ESI) m/z: 331.1 (M+H)⁺.

Intermediate 656B:(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanone

Intermediate 656A (1.28 g, 3.86 mmol), lithium chloride (0.164 g, 3.86mmol), copper(II) chloride (0.519 g, 3.86 mmol), and tert-butyl nitrite(0.461 mL, 3.86 mmol) were dissolved in MeCN (38.6 mL). After 3 hours,the reaction mixture was diluted with EtOAc, washed with 1 N HCl,saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The crude material was purified by column chromatography(ISCO, 40 g silica gel column, 19 minute gradient from 0 to 100% EtOAcin hexanes) to give Intermediate 656B (386 mg, 1.1 mmol, 29% over 2steps): ¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J=2.4 Hz, 1H), 7.12 (d, J=2.4Hz, 1H), 3.91 (s, 3H), 3.01-2.89 (m, 2H), 2.66-2.56 (m, 2H), 2.23-2.09(m, 1H), 2.06-1.92 (m, 1H); LC-MS: Method H, RT=1.18 min, MS (ESI) m/z:350.1 (M+H)⁺.

Intermediate 656C:(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanol

Intermediate 656B (386 mg, 1.104 mmol) was suspended in MeOH (5.52 mL)and cooled to 0° C. Sodium borohydride (84 mg, 2.21 mmol) was thenadded. After 45 minutes, the reaction mixture was diluted with water andextracted with EtOAc. The organic layer was washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 40 g silica gel column, 19minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate656C (314 mg, 0.891 mmol, 81%) as a yellow oil: ¹H NMR (400 MHz, CDCl₃)δ 7.21 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 5.31 (d, J=8.6 Hz,1H), 4.28 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 2.69-2.59 (m, 1H), 2.39-2.25(m, 2H), 2.24-2.14 (m, 1H), 1.99-1.86 (m, 1H), 1.69-1.59 (m, 1H); LC-MS:Method H, RT=1.13 min, MS (ESI) m/z: 352.1 (M+H)⁺.

Intermediate 656D:(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanol

Intermediate 656C (314 mg, 0.891 mmol) was purified by chiral SFC(Chiralpak OJ-H, 30×250 mm, 5 micron, 5% MeOH/95% CO₂, 70 mL/min, 150bar, 40° C.) to give Intermediate 656D (136 mg, 0.386 mmol, 43%, 87.8%ee): ¹H NMR and LCMS data was identical to Intermediate 656C.

Example 656

Intermediate I-121 (20 mg, 0.063 mmol), Intermediate 656D (22 mg, 0.063mmol) and PdCl₂(dppf) (2.75 mg, 3.75 μmol) were dissolved in 1,4-dioxane(626 μL) and Na₂CO₃ (2 M, 282 μL, 0.563 mmol) and heated to 100° C.After 2 hours, the reaction mixture was cooled to ambient temperatureand concentrated in vacuo. The crude material was purified bypreparative HPLC (Method D, 60-100% B in 20 minutes) to give Example 656(6.7 mg, 0.013 mmol, 21%): ¹H NMR (500 MHz, DMSO-d₆) δ 8.88 (d, J=2.4Hz, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.69 (s,1H), 7.33 (s, 1H), 5.94 (s, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 3.42-3.36(m, 1H), 2.70 (d, J=8.5 Hz, 1H), 2.21-2.12 (m, 2H), 2.09 (d, J=5.8 Hz,1H), 1.83 (d, J=9.8 Hz, 1H), 1.56 (dd, J=10.5, 5.3 Hz, 1H); LC-MS:Method H, RT=1.32 min, MS (ESI) m/z: 509.0 (M+H)⁺; Analytical HPLCMethod B, 100% purity.

Example 657(2R,3S)-3-((2-(3,6-dimethoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate 657A: 5-methoxy-2-nitrobenzoyl chloride

5-methoxy-2-nitrobenzoic acid (3.9 g, 19.78 mmol) was dissolved in DCM(39.6 mL). Oxalyl chloride (13.8 mL, 27.7 mmol) and then DMF (0.153 mL,1.98 mmol) were added at ambient temperature. After 1.5 hours, thereaction mixture was concentrated in vacuo to give Intermediate 657A,which was used directly in the subsequent step.

Intermediate 657B: ethyl 5-methoxy-2-nitrobenzoate

Intermediate 657A (4.26 g, 19.8 mmol) was dissolved in sodium methoxide(0.5 M in MeOH, 59.3 mL, 29.6 mmol). THF (60 mL) was added to aidsolubility. After stirring overnight, the reaction mixture wasconcentrated in vacuo, diluted with EtOAc and washed with water, thenbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo to giveIntermediate 657B (3.43 g, 15.2 mmol, 77%) as a yellow oil (Note, finalextraction solution was allowed to sit overnight and the methyl esterswapped to the ethyl ester at that point): ¹H NMR (400 MHz, CDCl₃) δ8.04 (d, J=9.0 Hz, 1H), 7.06-7.04 (m, 1H), 7.04-6.99 (m, 1H), 4.41 (q,J=7.0 Hz, 2H), 3.92 (s, 3H), 1.37 (t, J=7.2 Hz, 3H)

Intermediate 657C: Ethyl 2-amino-5-methoxybenzoate

Intermediate 657B (3.43 g, 15.2 mmol) was dissolved in EtOH (21.8 mL).Palladium on carbon (0.324 g, 0.305 mmol) and then ammonium formate(4.80 g, 76 mmol) were added and the reaction mixture was heated toreflux. After 3 hours, the reaction mixture was filtered through celiteand concentrated in vacuo to give Intermediate 657C (2.85 g, 14.6 mmol,96%) as an orange oil: ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J=3.1 Hz, 1H),6.95 (dd, J=8.9, 3.0 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 5.40 (br. s., 2H),4.34 (q, J=7.3 Hz, 2H), 3.77 (s, 3H), 1.39 (t, J=7.2 Hz, 3H); LC-MS:Method H, RT=0.76 min, MS (ESI) m/z: 196 (M+H)⁺.

Intermediate 657D: ethyl 2-amino-3-bromo-5-methoxybenzoate

Intermediate 657C (0.5 g, 2.56 mmol) and NBS (0.456 g, 2.56 mmol) weredissolved in AcOH (5.12 mL). After 3 hours, the reaction was quenchedwith vigorous stirring with saturated NaHCO₃. The layers were separatedand the organic layer was further washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 40 g silica gel column, 27minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate657D (236 mg, 0.861 mmol, 34%) as a yellow oil: ¹H NMR (500 MHz, CDCl₃)δ 7.46 (d, J=2.8 Hz, 1H), 7.30 (d, J=3.0 Hz, 1H), 5.98 (br. s., 2H),4.38 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); LC-MS:Method H, RT=1.05 min, MS (ESI) m/z: 274/276 (M+H)⁺.

Intermediate 657E: (2-amino-3-bromo-5-methoxyphenyl)methanol

Intermediate 657D (236 mg, 0.861 mmol) was dissolved in THF (2.87 mL).Lithium borohydride (37.5 mg, 1.72 mmol) was added and the reactionmixture was heated to 50° C. After 2 hours, the reaction mixture wasdiluted with water and stirred for 30 minutes. All of the lithiumborohydride had not dissolved, so concentrated HCl was added carefullyto speed up the quenching process. The reaction mixture was thenextracted three times with EtOAc. The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuoto give Intermediate 657E (188 mg, 0.808 mmol, 94%) as an orange solid:¹H NMR (400 MHz, CDCl₃) δ 7.03 (d, J=2.9 Hz, 1H), 6.71 (d, J=2.9 Hz,1H), 4.68 (s, 2H), 4.35 (br. s., 2H), 3.76 (s, 3H), 1.72 (br. s., 1H);LC-MS: Method H, RT=0.68 min, MS (ESI) m/z: 232/234 (M+H)⁺.

Intermediate 657F: 2-amino-3-bromo-5-methoxybenzaldehyde

Intermediate 657E (186 mg, 0.801 mmol) was dissolved in CHCl₃ (5.34 mL).Manganese dioxide (418 mg, 4.81 mmol) was added and the reaction mixturewas heated to 40° C. After heating overnight, the reaction mixture wasfiltered through celite and concentrated in vacuo to give Intermediate657F (167 mg, 0.724 mmol, 90%) as a red solid: ¹H NMR (400 MHz, CDCl₃) δ9.82 (s, 1H), 7.36 (d, J=2.9 Hz, 1H), 7.04 (d, J=2.9 Hz, 1H), 6.35 (br.s., 2H), 3.82 (s, 3H); LC-MS: Method H, RT=0.90 min, MS (ESI) m/z:230/232 (M+H)⁺.

Intermediate 657G: 3-(benzyloxy)-8-bromo-6-methoxyquinoline

Intermediate 657F (165 mg, 0.717 mmol), 2-(benzyloxy)acetaldehyde (108mg, 0.717 mmol), and sodium methoxide (0.5 M in MeOH, 1.58 mL, 0.789mmol) were dissolved in MeOH (2.87 mL) and heated to reflux. Afterheating overnight, the reaction mixture was diluted with saturatedNH₄Cl, partially concentrated in vacuo and diluted with EtOAc. Thelayers were separated and the organic layer was washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (ISCO, 24 g silica gel column, 19minute gradient from 0 to 100% EtOAc in hexanes) to give Intermediate657G (210 mg, 0.610 mmol, 85%): LC-MS: Method H, RT=1.10 min, MS (ESI)m/z: 344/346 (M+H)⁺.

Intermediate 657H: 8-bromo-6-methoxyquinolin-3-ol, HCl

Intermediate 657G (210 mg, 0.610 mmol) and pentamethylbenzene (633 mg,4.27 mmol) were dissolved in DCM (12.2 mL) and cooled to −78° C. Borontrichloride (1 M in heptane, 1.59 mL, 1.59 mmol) was then added and thereaction mixture was allowed to warm slowly to ambient temperature.After stirring overnight, the reaction mixture was diluted with hexanesand 1 N HCl and allowed to stir for 1 hour. The solid was collected bysuction filtration to give Intermediate 657H (38.9 mg, 0.134 mmol, 22%)as a brown solid: ¹H NMR (400 MHz, MeOH₄) δ 8.54 (d, J=2.6 Hz, 1H), 8.01(d, J=2.4 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 3.97(s, 3H); LC-MS: Method H, RT=0.77 min, MS (ESI) m/z: 254/256 (M+H)⁺.

Intermediate 657I: 8-bromo-3,6-dimethoxyquinoline

Intermediate 657H (38.9 mg, 0.134 mmol), K₂CO₃ (55.5 mg, 0.402 mmol),and methyl iodide (16.7 μL, 0.268 mmol) were dissolved in acetone (1.34mL) and heated to 50° C. in a sealed tube. After heating overnight, thereaction mixture was diluted with EtOAc, washed with water, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate657I (32 mg, 0.119 mmol, 89%) as a tan solid: ¹H NMR (400 MHz, CDCl₃) δ8.55 (d, J=2.6 Hz, 1H), 7.51 (d, J=2.6 Hz, 1H), 7.22 (d, J=2.9 Hz, 1H),6.93 (d, J=2.6 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H); LC-MS: Method H,RT=0.93 min, MS (ESI) m/z: 268/270 (M+H)⁺.

Intermediate 657J:3,6-dimethoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline

Intermediate 657I (32 mg, 0.119 mmol), bispinacolatodiboron (60.6 mg,0.239 mmol), potassium acetate (29.3 mg, 0.298 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (7.80 mg, 9.55 μmol) were stored on HIVAC for15 minutes, then were dissolved in 1,4-dioxane (597 μL), and degassedfor 15 minutes by bubbling with argon. The reaction mixture was heatedto 130° C. in the microwave for 40 minutes. The reaction mixture wasdiluted with EtOAc and washed with water then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate 657J, which wasused directly in the subsequent reaction: LC-MS: Method H, RT=0.66 min,MS (ESI) m/z: 234.2 (boronic acid mass observed, M+H)⁺.

Example 657

Intermediate 657J (18 mg, 0.057 mmol), Intermediate I-130 (23.5 mg,0.057 mmol) and PdCl₂(dppf) (2.51 mg, 3.43 μmol) were dissolved in1,4-dioxane (571 μL) and Na₂CO₃ (2 M, 257 μL, 0.514 mmol) and heated to100° C. After 2 hours, the reaction mixture was cooled to ambienttemperature. The reaction mixture was concentrated in vacuo. The crudematerial was purified by preparative HPLC (Method D, 45-90% B in 20minutes) to give Example 657 (6.2 mg, 0.011 mmol, 19%): ¹H NMR (500 MHz,DMSO-d₆) δ 9.96 (br. s., 1H), 8.82-8.64 (m, 3H), 8.33 (br. s., 1H), 8.04(d, J=7.9 Hz, 1H), 7.96 (d, J=11.6 Hz, 1H), 7.87 (br. s., 1H), 7.55 (br.s., 1H), 5.12 (d, J=4.9 Hz, 1H), 4.81 (br. s., 1H), 3.99 (s, 6H), 2.56(s, 3H), 1.40 (d, J=5.8 Hz, 6H); LC-MS: Method H, RT=1.12 min, MS (ESI)m/z: 565.9 (M+H)⁺; Analytical HPLC Method B, 100% purity.

Example 6582-((4-(1-hydroxy-2,2-dimethylpropyl)-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-6-yl)oxy)ethylpyridin-4-ylcarbamate

Intermediate 658A:1-(2-chloro-6-(2-hydroxyethoxy)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 638D (19.4 mg, 0.055 mmol) was dissolved in toluene (363μL) and THF (182 μL) and cooled to −78° C. DIBAL-H (1 M in toluene, 164μL, 0.164 mmol) was then added and the reaction mixture was allowed towarm slowly to ambient temperature. After stirring overnight, another 50μL of DIBAL was then added. After 2.5 hours, the reaction was quenchedwith a saturated solution of Rochelle's salt. The reaction mixture wasextracted with EtOAc. The organic layer was further washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate658A (28.3 mg, 0.090 mmol, 100%) as an orange oil, which was useddirectly in the subsequent reaction: LC-MS: Method H, RT=0.97 min, MS(ESI) m/z: 316.2 (M+H)⁺.

Intermediate 658B:2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)ethylcarbonochloridate

Intermediate 658A (24 mg, 0.076 mmol) and phosgene solution (15% intoluene, 268 μL, 0.380 mmol) were dissolved in THF (760 μL). After 30minutes, the reaction mixture was concentrated in vacuo to giveIntermediate 658B, which was used directly in the subsequent reaction:LC-MS: Method H, RT=1.17 min, MS (ESI) m/z: 378.0 (M+H)⁺.

Intermediate 658C:2-((2-chloro-4-(1-hydroxy-2,2-dimethylpropyl)benzo[d]thiazol-6-yl)oxy)ethylpyridin-4-ylcarbamate

Intermediate 658B (14 mg, 0.037 mmol), pyridin-4-amine (12.2 mg, 0.130mmol), and diisopropylethylamine (64.6 μL, 0.370 mmol) were dissolved inDCM (740 μL.) After 30 minutes, the reaction mixture was concentrated invacuo to give Intermediate 658C, which was used directly in thesubsequent step: LC-MS: Method H, RT=0.87 min, MS (ESI) m/z: 436.1(M+H)⁺.

Example 658

Intermediate I-9 (13.2 mg, 0.044 mmol) and Intermediate 658C (16 mg,0.037 mmol) were dissolved in DMF (367 μL). PdCl₂(dppf)-CH₂Cl₂ adduct(1.8 mg, 2.2 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Sodium carbonate (2 M, 22 μL, 0.044mmol) was added and the reaction mixture was degassed for 5 minutes,then sealed and heated to 100° C. in the microwave for 30 minutes. Thecrude material was purified by preparative HPLC (Method D, 55-100% B in20 minutes) to give Example 658 (3.3 mg, 0.0057 mmol, 16%): ¹H NMR (500MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.38 (d,J=5.8 Hz, 2H), 7.81 (s, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.45 (d, J=6.1 Hz,2H), 7.15 (d, J=2.1 Hz, 1H), 5.42 (d, J=4.6 Hz, 1H), 5.31 (d, J=4.9 Hz,1H), 4.53 (br. s., 2H), 4.42-4.23 (m, 2H), 4.07 (s, 3H), 3.35 (s, 1H),2.64 (s, 3H), 0.94 (s, 9H); LC-MS: Method H, RT=1.08 min, MS (ESI) m/z:574.2 (M+H)⁺; Analytical HPLC Method B, 99% purity.

Example 659(2R,3S)-3-((2-(3-(difluoromethoxy)-6-methylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate 659A: 8-bromo-3-(difluoromethoxy)-6-methylquinoline

Intermediate I-125E (100 mg, 0.42 mmol) and K₂CO₃ (290 mg, 2.1 mmol)were suspended in DMF (4.2 mL) and heated to 100° C. Sodium2-chloro-2,2-difluoroacetate (256 mg, 1.68 mmol) was then added. After1.5 hours, the reaction mixture was cooled to ambient temperature,diluted with water, and thrice extracted with EtOAc. The combinedorganic extracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 24 g silica gel column, 19 minute gradient from 0to 50% EtOAc in hexanes) to give Intermediate 659A (58 mg, 0.201 mmol,48%): ¹H NMR (500 MHz, CDCl₃) δ 8.85 (d, J=2.5 Hz, 1H), 7.93 (d, J=1.7Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.56 (s, 1H), 6.88-6.47 (m, 1H), 2.56(s, 3H); LC-MS: Method H, RT=1.08 min, MS (ESI) m/z: 288/290 (M+H)⁺.

Intermediate 659B:3-(difluoromethoxy)-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate 659A (58 mg, 0.201 mmol), bispinacolatodiboron (102 mg,0.403 mmol), potassium acetate (49.4 mg, 0.503 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (13.2 mg, 0.016 mmol) were stored on HIVAC for15 minutes then were dissolved in dry 1,4-dioxane (1.01 mL) and degassedfor 15 minutes by bubbling with argon. The reaction mixture was heatedto 130° C. in the microwave for 40 minutes. The reaction mixture wasdiluted with EtOAc and washed with water then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate 659B, which wasused directly in the subsequent reaction: LC-MS: Method H, RT=0.82 min,MS (ESI) m/z: 254.0 (boronic acid mass observed, M+H)⁺.

Example 659

Intermediate 659B (15 mg, 0.045 mmol), Intermediate I-130 (18.4 mg,0.045 mmol) and PdCl₂(dppf) (1.96 mg, 2.69 μmol) were dissolved in1,4-dioxane (448 μL) and Na₂CO₃ (2 M, 201 μL, 0.403 mmol) and heated to100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature and concentrated in vacuo. The crude material was purifiedby preparative HPLC (Method D, 45-90% B in 20 minutes) to give Example659 (8.7 mg, 0.015 mmol, 33%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br. s.,1H), 8.98 (br. s., 1H), 8.77 (br. s., 1H), 8.74 (br. s., 2H), 8.29 (br.s., 1H), 8.06 (d, J=7.6 Hz, 1H), 8.00 (br. s., 1H), 7.96 (d, J=11.3 Hz,1H), 7.66-7.32 (m, 1H), 5.12 (d, J=6.4 Hz, 1H), 4.82 (d, J=5.8 Hz, 1H),2.64 (s, 3H), 2.55 (s, 3H), 1.40 (br. s., 6H); LC-MS: Method H, compounddid not ionize; Analytical HPLC Method B, 100% purity.

Example 660(2R,3S)-3-((2-(3-ethoxy-6-methylquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate 660A: 8-bromo-3-ethoxy-6-methylquinoline

Intermediate I-125E (100 mg, 0.364 mmol), K₂CO₃ (151 mg, 1.09 mmol), andiodoethane (114 mg, 0.728 mmol) were dissolved in acetone (3.64 mL) andheated to 50° C. in a sealed tube. After heating overnight, the reactionmixture was diluted with EtOAc, washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give Intermediate 660A(105 mg, 0.394 mmol, 100%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ8.73 (d, J=2.9 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.46 (s, 1H), 7.30 (d,J=2.9 Hz, 1H), 4.19 (q, J=7.0 Hz, 2H), 2.52 (s, 3H), 1.54 (t, J=6.9 Hz,3H); LC-MS: Method H, RT=1.14 min, MS (ESI) m/z: 266/268 (M+H)⁺.

Intermediate 660B:3-ethoxy-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Intermediate 660A (100 mg, 0.376 mmol), bispinacolatodiboron (191 mg,0.752 mmol), potassium acetate (92 mg, 0.939 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (24.6 mg, 0.030 mmol) were stored on HIVAC for15 minutes then were dissolved in dry 1,4-dioxane (1.88 mL) and degassedfor 15 minutes by bubbling with argon. The reaction mixture was heatedto 130° C. in the microwave for 40 minutes. The reaction mixture wasdiluted with EtOAc and washed with water then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to give Intermediate 660B, which wasused directly in the subsequent reaction: LC-MS: Method H, RT=0.70 min,MS (ESI) m/z: 232.0 (boronic acid mass observed, M+H)⁺.

Example 660

Intermediate 660B (15 mg, 0.048 mmol), Intermediate I-130 (19.7 mg,0.048 mmol) and PdCl₂(dppf) (2.1 mg, 2.87 μmol) were dissolved in1,4-dioxane (479 μL) and Na₂CO₃ (2 M, 216 μL, 0.431 mmol) and heated to100° C. After 1 hour, the reaction mixture was cooled to ambienttemperature and concentrated in vacuo. The crude material was purifiedby preparative HPLC (Method D, 50-100% B in 15 minutes) to give Example660 (7.2 mg, 0.013 mmol, 27%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br. s.,1H), 8.77 (br. s., 1H), 8.74 (br. s., 2H), 8.60 (br. s., 1H), 8.04 (d,J=7.9 Hz, 1H), 7.94 (d, J=11.6 Hz, 1H), 7.85 (br. s., 2H), 5.11 (d,J=6.1 Hz, 1H), 4.80 (d, J=5.5 Hz, 1H), 4.33-4.20 (m, 2H), 2.61 (s, 3H),2.55 (s, 3H), 1.46 (t, J=6.6 Hz, 3H), 1.40 (d, J=5.5 Hz, 6H); LC-MS:Method H, RT=1.04 min, MS (ESI) m/z: 562.2 (M+H)⁺; Analytical HPLCMethod B, 100% purity.

Example 661 5-(benzofuran-2-yl)-2-ethoxy-7-methylquinoxaline

Intermediate 661A: tert-butylN-(2-bromo-4-methyl-6-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate

2-Bromo-4-methyl-6-nitroaniline (3 g, 12.98 mmol), DMAP (0.159 g, 1.298mmol), and Boc₂O (7.54 ml, 32.5 mmol) were dissolved in THF (21.64 ml)and allowed to stir overnight. The reaction mixture was diluted withwater and extracted with EtOAc. The organic layer was washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude materialwas purified by column chromatography (ISCO, 80 g silica gel column, 29minute gradient from 0 to 50% EtOAc in hexanes) to yield Intermediate661A (5.41 g, 12.54 mmol, 97% yield) as a yellow solid. ¹H NMR (400 MHz,MeOH₄) δ 7.90 (s, 2H), 2.47 (s, 3H), 1.36 (s, 18H). LC-MS: method H,RT=1.10 min, compound does not ionize.

Intermediate 661B: methyl2-((2-bromo-4-methyl-6-nitrophenyl)(tert-butoxycarbonyl)amino)acetate

Intermediate 661A (5.41 g, 12.54 mmol) was dissolved in DCM (20.91 ml)and TFA (1.933 ml, 25.09 mmol) was added. The reaction mixture wasstirred at room temperature for 45 min. The reaction mixture was dilutedwith DCM, quenched with saturated NaHCO₃, washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The crude material wasredissolved in DMF (20.91 ml). Cs₂CO₃ (10.22 g, 31.4 mmol) was added andstirred for 15 minutes. Methyl bromoacetate (1.387 ml, 15.05 mmol) wasadded and stirred for an additional 15 min. The reaction mixture wasdiluted with EtOAc, washed with water, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 120 g silica gel column, 29 minute gradientfrom 0 to 50% EtOAc in hexanes) to yield Intermediate 661B (4.58 g,11.36 mmol, 91% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ7.79-7.54 (m, 2H), 4.55 (d, J=17.3 Hz, 1H), 4.00 (s, 1H), 3.68 (s, 3H),2.43 (s, 3H), 1.56-1.53 (m, 3H), 1.42-1.33 (m, 9H). LC-MS: method H,RT=1.02 min, compound does not ionize.

Intermediate 661C: methyl2-((2-bromo-4-methyl-6-nitrophenyl)amino)acetate

Intermediate 661B (4.58 g, 11.36 mmol) was dissolved in HCl in dioxanes(14.20 ml, 56.8 mmol) and stirred at room temperature for 5h. Thereaction mixture was concentrated to yield Intermediate 661C (3.55 g,11.71 mmol, 100% yield) as a yellow solid. Used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J=2.8 Hz, 2H), 4.56 (d,J=17.3 Hz, 1H), 4.05 (d, J=17.6 Hz, 1H), 3.69 (s, 3H), 2.43 (s, 3H).LC-MS: method H, RT=0.97 min, MS (ESI) m/z: 303.1 (M+H)⁺.

Intermediate 661D: 5-bromo-7-methyl-3,4-dihydroquinoxalin-2(1H)-one

Intermediate 661C (3.55 g, 11.71 mmol) was dissolved in MeOH (42.6 ml).Concentrated HCl (3.90 ml, 46.8 mmol) then tin(II) chloride dihydrate(10.57 g, 46.8 mmol) were added and the reaction heated to 65° C. for2.5 h. The reaction mixture was cooled to ambient temperature,neutralized with 10 N NaOH and diluted with brine and EtOAc. The mixturewas filtered through celite and the layers separated. The organic layerwas washed with saturated NaHCO₃, then brine, dried (Na₂SO₄), filtered,and concentrated in vacuo to yield Intermediate 661D (2.30 g, 9.54 mmol,81%). ¹H NMR (400 MHz, CDCl₃) δ 8.75 (br. s., 1H), 6.95 (s, 1H), 6.52(s, 1H), 4.29 (br. s., 1H), 4.04 (d, J=1.3 Hz, 2H), 2.22 (s, 3H). LC-MS:method H, RT=0.78 min, MS (ESI) m/z: 241.1 (M+H)⁺.

Intermediate 661E: 5-bromo-7-methylquinoxalin-2(1H)-one

Intermediate 661D (2.30 g, 9.54 mmol) was suspended in MeOH (27.7 ml).NaOH (28.6 ml, 28.6 mmol) then H₂O₂ (5.01 ml, 57.2 mmol) were added andthe reaction mixture was allowed to stir at room temperature for 48 h.The reaction was quenched with saturated Na₂SO₃. The reaction was thendiluted with saturated NaHCO₃ and extracted thrice with EtOAc. Thecombined organic layers were filtered through celite, washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. Compound was thentriturated with EtOAc to yield Intermediate 661E (1.32 g, 5.52 mmol,57.9% yield) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s,1H), 7.49 (s, 1H), 7.09 (s, 1H), 2.40 (s, 3H). LC-MS: method H, RT=0.75min, MS (ESI) m/z: 239.0 (M+H)⁺.

Intermediate 661F: 5-bromo-2-ethoxy-7-methylquinoxaline

Intermediate 661E (0.050 g, 0.209 mmol) was dissolved in DMF (1 mL). Tothis solution was added Cs₂CO₃ (0.341 g, 1.046 mmol), and the reactionmixture was allowed to stir for 5 min. Iodoethane (0.017 mL, 0.209 mmol)was then added, and the reaction mixture was allowed to room temperaturefor 48 hours. The reaction mixture was diluted with water and EtOAc. Thelayers were separated and the organic layer was washed with brine, driedwith sodium sulfate and concentrated under reduced pressure. Purified onPrep HPLC using Solvent A: 10% MeOH/90% H₂O/0.1% TFA and Solvent B 90%MeOH/10% H₂O/0.1% TFA on Phenomenex AXIA C18 30×100 mm with a 10 mingradient and 5 min hold time with a flow rate of 40 mL/min to yieldIntermediate 661F (0.012 g, 0.045 mmol, 21.48% yield) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 7.52-7.47 (m, 1H), 7.11 (s, 1H),4.30 (q, J=7.2 Hz, 2H), 2.51 (s, 3H), 1.38 (t, J=7.2 Hz, 3H). LC-MS:method H, RT=0.87 min, MS (ESI) m/z: 267.0 (M+H)⁺.

Example 661

Intermediate 661F (0.012 g, 0.045 mmol) and benzofuran-2-ylboronic acid(10.91 mg, 0.067 mmol) were dissolved in toluene (0.674 ml) and EtOH(0.225 ml). PdCl₂(dppf)-CH₂Cl₂ adduct (2.201 mg, 2.70 μmol) was addedand the reaction degassed by bubbling with argon for 15 minutes. Na₂CO₃(0.027 ml, 0.054 mmol) was added and the reaction degassed for 5minutes, then sealed and heated to 120° C. in the microwave for 30minutes. The reaction mixture was diluted with EtOAc, filtered through amicron filter, and concentrated in vacuo. The crude material waspurified by Prep LC (Axia Luna 5 u C18 30×100 mm column, 10 minutegradient from 20 to 100% B in A, A=10:90:0.1 MeOH:H₂O:TFA, B=90:10:0.1MeOH:H₂O:TFA) to yield Example 661 (0.88 mg, 2.75 μmol, 6.11% yield) asa tan solid. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 8.13 (d, J=2.0 Hz,1H), 8.07 (d, J=0.8 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.60 (d, J=1.0 Hz,1H), 7.56 (d, J=8.8 Hz, 1H), 7.35-7.29 (m, 1H), 7.28-7.22 (m, 1H), 4.56(q, J=7.0 Hz, 2H), 2.62 (s, 3H), 1.50 (t, J=7.2 Hz, 3H). LC-MS: methodH, RT=1.31 min, MS (ESI) m/z: 305.1 (M+H)⁺.

Example 662 4-methoxyphenyl(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate

Intermediate 662A: tert-butyl(2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate

Intermediate I-138A (0.250 g, 0.729 mmol) was dissolved in DMF (7.29ml). tert-Butyl (2-bromoethyl)carbamate (0.196 g, 0.875 mmol) and Cs₂CO₃(1.187 g, 3.64 mmol) were added and the reaction mixture was stirred at40° C. overnight. The reaction mixture was diluted with EtOAc and waterand the layers were separated. The organic layer was washed with brine,dried with sodium sulfate, and concentrated under reduced pressure. Thereaction was purified on ISCO using a 40 g column with a 0-100% EtOAc inhexanes gradient to yield Intermediate 662A (0.074 g, 0.228 mmol, 31.3%yield) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 6.54 (s, 1H),5.01 (br. s., 2H), 4.33 (t, J=5.2 Hz, 2H), 3.52 (d, J=4.8 Hz, 2H), 2.49(d, J=0.7 Hz, 3H), 1.45 (s, 9H), 1.28-1.24 (m, 1H). LC-MS: method H,RT=0.83 min, MS (ESI) m/z: 325.2 (M+H)⁺.

Intermediate 662B: tert-butyl(2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate

Copper(II) bromide (0.087 g, 0.388 mmol) and t-butyl nitrite (0.046 ml,0.388 mmol) were dissolved in MeCN (0.912 ml) and allowed to stir 10minutes. Intermediate 662A (0.074 g, 0.228 mmol) was dissolved in MeCN(1.369 ml) and the copper solution was added. The reaction mixture wasdiluted with EtOAc, washed with 1 N HCl, saturated NaHCO₃, then brine,dried (Na+SO₄), filtered, and concentrated in vacuo to yieldIntermediate 662B (0.080 g, 0.206 mmol, 90% yield). ¹H NMR (400 MHz,CDCl₃) δ 6.66 (d, J=0.9 Hz, 1H), 4.39 (t, J=5.3 Hz, 2H), 3.54 (d, J=5.1Hz, 2H), 2.63 (d, J=0.9 Hz, 3H), 1.45 (s, 9H). LC-MS: method H, RT=1.13min, MS (ESI) m/z: 388.1 (M+H)⁺.

Intermediate 662C: tert-butyl(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)carbamate

Intermediate I-9 (0.062 g, 0.206 mmol) and Intermediate 662B (0.080 g,0.206 mmol) were dissolved in DMF (1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(10.10 mg, 0.012 mmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100 ml, 0.300mmol) was added and the reaction degassed for 5 minutes, then sealed andheated to 90° C. in the microwave for 30 minutes. The reaction mixturewas filtered and purified on 24 g ISCO column with 0-100% EtOAc inhexanes gradient to yield Intermediate 662C (0.048 g, 0.100 mmol, 48.4%yield) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J=2.0Hz, 1H), 8.54 (s, 1H), 7.77-7.72 (m, 1H), 6.70 (d, J=0.7 Hz, 1H), 4.47(t, J=5.2 Hz, 2H), 4.12 (s, 3H), 3.58 (d, J=4.8 Hz, 2H), 2.79 (d, J=0.7Hz, 3H), 2.66 (s, 3H), 1.53 (s, 9H). LC-MS: method H, RT=1.36 min, MS(ESI) m/z: 482.1 (M+H)⁺.

Intermediate 662D:2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethanamine

To a mixture of Intermediate 662C (0.048 g, 0.100 mmol) in DCM (1) wasadded 2,6-lutidine (0.035 ml, 0.299 mmol) followed by TMS-OTf (0.072 ml,0.399 mmol) at room temperature. The mixture was stirred at roomtemperature for 1 h. The mixture was diluted with NaHCO₃ and extractedby EtOAc. The combined organic layer was washed by brine, dried bysodium sulfate and concentrated to yield Intermediate 662D (0.036 g,0.094 mmol, 95% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J=1.5 Hz,1H), 8.53 (s, 1H), 7.74 (d, J=0.9 Hz, 1H), 6.72 (d, J=0.9 Hz, 1H), 4.44(t, J=5.3 Hz, 2H), 4.12 (s, 3H), 3.12 (t, J=5.3 Hz, 2H), 2.79 (d, J=0.9Hz, 3H), 2.66 (s, 3H). LC-MS: method H, RT=1.08 min, MS (ESI) m/z: 382.1(M+H)⁺.

Example 662

Intermediate 662D (0.020 g, 0.052 mmol) was dissolved in DCM (0.350 ml)and THF (0.175 ml). To the solution was added 4-methoxyphenylcarbonochloridate (0.029 g, 0.157 mmol) followed by DIEA (0.092 ml,0.524 mmol). The solution was allowed to stir at room temperatureovernight. The reaction mixture was concentrated and suspended in 2 mLof hot DMSO, filtered, and purified by preparative HPLC (Method D, 70%to 100% B in 20 minutes) to yield Example 662 (0.0027 g, 5.08 mol, 9.69%yield): MS (ESI) m/z: 532.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.76(br. s., 1H), 8.59 (br. s., 1H), 7.94-7.85 (m, 2H), 7.03 (d, J=8.0 Hz,2H), 6.79-6.67 (m, 2H), 4.47 (br. s., 2H), 4.11 (br. s., 3H), 3.76 (br.s., 4H), 3.67 (br. s., 2H), 2.77 (br. s., 3H), 2.67 (br. s., 3H). LC-MS:method H, RT=1.45 min, MS (ESI) m/z: 532.1 (M+H)⁺. Analytical HPLCMethod B: 100% purity.

Example 663(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol

Intermediate 663A:(2-amino-6-methoxybenzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol

Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1930 μl).NaH (8.49 mg, 0.212 mmol) was added and the reaction mixture was stirredfor 5 min. The reaction mixture was cooled to −78° C. and BuLi (101 μl,0.232 mmol) was added and allowed to stir for 30 min.Tetrahydro-2H-pyran-4-carbaldehyde (44.0 mg, 0.386 mmol) was added andthe reaction mixture was allowed to warm to ambient temperature. Thereaction mixture was diluted with EtOAc and washed with water, thenbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo to yieldIntermediate 663A (0.05 g, 0.170 mmol, 88%). Used without furtherpurification. LC-MS: method H, RT=0.56 min, MS (ESI) m/z: 295.2 (M+H)⁺.

Intermediate 663B:(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol

Copper(II) chloride (0.044 g, 0.329 mmol) and t-butyl nitrite (0.039 ml,0.329 mmol) were dissolved in MeCN (0.775 ml) and allowed to stir 10minutes. Intermediate 663A (0.057 g, 0.194 mmol) was dissolved in MeCN(1.162 ml) and the copper solution was added. The reaction mixture wasstirred for 2.5h at 60° C. The reaction mixture was diluted with EtOAc,washed with 1 N HCl, saturated NaHCO₃, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purified on ISCO using 0-100% EtOAcin hexanes gradient on a 24 g column to yield Intermediate 663B (0.020g, 0.064 mmol, 32.9% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.15 (d, J=2.4Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 4.72 (t, J=7.6 Hz, 1H), 3.97 (d, J=6.6Hz, 2H), 3.87 (s, 3H), 3.46-3.34 (m, 3H), 3.27 (td, J=11.8, 2.2 Hz, 1H),1.28-1.23 (m, 2H), 0.94-0.81 (m, 2H). LC-MS: method H, RT=0.56 min, MS(ESI) m/z: 314.1 (M+H)⁺.

Example 663

Intermediate I-9 (9.57 mg, 0.032 mmol) and Intermediate 663B (0.010,0.032 mmol) were dissolved in DMF (1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(1.561 mg, 1.912 μmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100 ml, 0.300mmol) was added and the reaction degassed for 5 minutes, then sealed andheated to 90° C. in the microwave for 30 minutes. The reaction mixturewas concentrated and suspended in 2 mL of hot DMSO, filtered, andpurified by preparative HPLC (Method D, 30% to 70% B in 25 minutes) toyield Example 663 (0.0044 g, 9.45 μmol, 29.7% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 8.73 (br. s., 1H), 8.54 (br. s., 1H), 7.82 (br. s., 1H), 7.59(br. s., 1H), 7.16 (br. s., 1H), 5.48-5.31 (m, 2H), 4.08 (br. s., 3H),3.88-3.86 (m, 3H), 3.78 (d, J=9.8 Hz, 1H), 3.27-3.16 (m, 2H), 2.64 (br.s., 3H), 2.00 (br. s., 1H), 1.71 (d, J=11.8 Hz, 1H), 1.45 (t, J=12.6 Hz,3H), 1.19 (d, J=12.5 Hz, 2H). LC-MS: method H, RT=1.45 min, MS (ESI)m/z: 452.2 (M+H)⁺. Analytical HPLC Method B: 97% purity.

Example 664(6-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanol

Intermediate 664A:(2-amino-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanone

Intermediate I-22 (50 mg, 0.193 mmol) was dissolved in THF (1930 μl).NaH (8.49 mg, 0.212 mmol) was added and the reaction mixture was stirredfor 30 min. The reaction mixture was cooled to −78° C. and BuLi (101 μl,0.232 mmol) was added and the reaction mixture was allowed to stir for30 min. Methyl 1-(trifluoromethyl) cyclobutanecarboxylate (35.1 mg,0.193 mmol) was added and the reaction mixture was allowed to warm toambient temperature. The reaction mixture was stirred for 10 min anddiluted with water and EtOAc. The layers were separated and the aqueouslayer was back extracted with EtOAc. The combined organic layer waswashed with water, dried with sodium sulfate, and concentrated underreduced pressure to yield Intermediate 664A (0.023 g, 0.191 mmol, 33%).LC-MS: method H, RT=0.77 min, MS (ESI) m/z: 331.2 (M+H)⁺.

Intermediate 664B:(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanone

Copper(II) chloride (0.042 g, 0.309 mmol) and t-butyl nitrite (0.037 ml,0.309 mmol) were dissolved in MeCN (0.727 ml) and allowed to stir 10minutes. Intermediate 664A (0.060 g, 0.182 mmol) was dissolved in MeCN(1.090 ml) and the copper solution was added. The reaction mixture wasstirred for 2.5 h at 60° C. The reaction mixture was diluted with EtOAc,washed with 1 N HCl, saturated NaHCO₃, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purified on ISCO using a 12 gcolumn with 0-100% gradient of EtOAc in hexanes to yield Intermediate664B (0.025 g, 0.036 mmol, 19.68% yield). LC-MS: method H, RT=1.12 min,MS (ESI) m/z: 350.1 (M+H)⁺.

Intermediate 664C:(2-chloro-6-methoxybenzo[d]thiazol-4-yl)(1-(trifluoromethyl)cyclobutyl)methanol

Intermediate 664B (0.035 g, 0.100 mmol) was dissolved in MeOH (1.00 ml)and cooled to 0° C. Sodium borohydride (3.79 mg, 0.100 mmol) was addedto the flask, and the reaction mixture was allowed to stir for 2h. Thereaction mixture was diluted with water and EtOAc. The layers wereseparated, and the aqueous layer was back extracted with EtOAc×3. Thecombined organic layer was washed with water, dried with sodium sulfate,and concentrated under reduced pressure to yield Intermediate 664C(0.030 g, 0.085 mmol, 85% yield) as a white solid. Used without furtherpurification. LC-MS: method H, RT=1.12 min, MS (ESI) m/z: 352.1 (M+H)⁺.

Example 664

Intermediate I-9 (0.065 g, 0.216 mmol) and Intermediate 664B (0.076 g,0.216 mmol) were dissolved in DMF (2.160 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(10.59 mg, 0.013 mmol) was added and the reaction degassed by bubblingwith argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100 ml, 0.300mmol) was added and the reaction degassed for 5 minutes, then sealed andheated to 90° C. in the microwave for 30 minutes. Enantiomers wereseparated using Lux 5 u Cellulose-4, 21×250 mm, 5 micron column with 35%EtOH/65% CO₂, UV 220 nm to afford Example 664 (10.7 mg, 0.021 mmol,9.61% yield) as a single enantiomer (99% enantiomeric excess). ¹H NMR(400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 7.77 (s, 1H),7.37 (d, J=2.4 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 5.81 (d, J=9.2 Hz, 1H),5.34 (d, J=9.2 Hz, 1H), 4.13 (s, 3H), 3.92 (s, 3H), 2.73 (s, 2H), 2.65(s, 3H), 2.35 (s, 4H), 1.88 (s, 1H). LC-MS: method H, RT=1.34 min, MS(ESI) m/z: 490.1 (M+H)⁺. Analytical HPLC Method B: 97% purity

Examples 665 to 677

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 663 or Example 664and the examples above.

LCMS LCMS Ex. [M + H]⁺ RT(Min)/ No. Structure m/z Method NMR 665

498.2 1.37/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.41 (s, 1H),7.78 (s, 1H), 7.46 (s, 1H), 7.11-7.07 (m, 2H), 6.99-6.94 (m, 1H), 6.90(d, J = 7.3 Hz, 2H), 6.48 (s, 1H), 5.94 (d, J = 4.9 Hz, 1H), 5.59 (d, J= 4.9 Hz, 1H), 4.06 (s, 3H), 3.66 (s, 3H), 2.75 (d, J = 7.3 Hz, 1H),2.65 (s, 4H), 2.25 (d, J = 9.2 Hz, 1H), 2.18-2.03 (m, 2H), 1.75 (br. s.,1H). 666

466.2 1.35/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (br. s., 1H), 8.56 (br.s., 1H), 7.81 (br. s., 1H), 7.59 (br. s., 1H), 7.15 (br. s., 1H), 5.67(br. s., 1H), 5.36 (br. s., 1H), 4.07 (br. s., 3H), 3.86 (br. s., 3H),3.43-3.38 (m, 2H), 3.17 (br. s., 3H), 2.63 (br. s., 3H), 2.35 (br. s.,1H), 2.23-2.13 (m, 1H), 1.74 (br. s., 4H). 667

476.1 1.29/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.53 (s, 1H),7.79 (s, 1H), 7.62 (s, 1H), 7.19 (s, 1H), 5.93-5.90 (m, 1H), 5.89-5.86(m, 1H), 4.06 (s, 3H), 3.86 (s, 3H), 2.60 (s, 3H), 1.22 (br. s., 1H),0.92 (br. s., 2H), 0.49 (d, J = 9.5 Hz, 1H). 668

484.2 1.27/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.45 (s, 1H),7.78 (s, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.20-7.00 (m, 5H), 6.73 (s, 1H),5.58 (d, J = 4.4 Hz, 1H), 5.51 (d, J = 4.0 Hz, 1H), 4.06 (s, 3H), 3.71(s, 3H), 2.65 (s, 3H), 1.37 (d, J = 4.4 Hz, 1H), 1.00 (d, J = 4.0 Hz,1H), 0.78- 0.65 (m, 2H). 669

490.1 1.34/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.45 (s, 1H),7.78 (s, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 5.98(d, J = 5.2 Hz, 1H), 5.92 (d, J = 5.2 Hz, 1H), 4.05 (s, 3H), 3.86 (s,3H), 2.58 (s, 3H), 2.21-2.01 (m, 2H), 1.80 (d, J = 10.4 Hz, 1H),1.67-1.53 (m, 1H), 1.20 (br. s., 1H), 0.80 (br. s., 1H). 671

476.1 1.29/H ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.49 (s, 1H), 7.77(s, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.72-5.64(m, 1H), 5.53 (s, 1H), 4.13 (s, 3H), 3.92 (s, 3H), 2.66 (s, 3H), 1.17(br. s., 1H), 1.02 (dt, J = 18.2, 5.7 Hz, 2H), 0.58 (d, J = 8.8 Hz, 1H)672

464.2 1.43   ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.47 (d, J = 1.5Hz, 1H), 7.75 (dd, J = 1.8, 0.9 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 6.91(d, J = 2.4 Hz, 1H), 5.84 (d, J = 9.1 Hz, 1H), 4.79 (d, J = 9.5 Hz, 1H),4.13 (s, 3H), 3.91 (s, 3H), 2.66 (s, 3H), 1.61 (br. s., 10H), 0.96 (s,3H). 673

451.0 1.15/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.50 (s, 1H),7.78 (s, 1H), 7.70-7.60 (m, 3H), 7.13 (s, 1H), 6.96 (br. s., 1H), 6.91(br. s., 1H), 4.06 (s, 3H), 3.84 (s, 3H), 2.61 (s, 3H). 674

466.2 1.23/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.49 (s, 1H),7.78 (s, 1H), 7.58 (s, 1H), 7.13 (s, 1H), 5.58-5.42 (m, 2H), 4.05 (s,3H), 3.85 (s, 3H), 3.77-3.59 (m, 3H), 3.42 (br. s., 1H), 2.61 (s, 3H),1.93-1.73 (m, 2H), 1.44 (br. s., 1H), 0.98 (s, 3H), 0.89-0.82 (m, 1H).675

492.1 1.29/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.66 (s, 1H),7.84 (s, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 7.01(d, J = 9.8 Hz, 1H), 6.72-6.64 (m, 2H), 6.32 (d, J = 4.3 Hz, 1H), 4.12(s, 3H), 3.91 (s, 3H), 3.78 (s, 3H), 2.68 (s, 3H). 676

464.2 1.39/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.52 (s, 1H),7.80 (s, 1H), 7.58 (br. s., 1H), 7.14 (br. s., 1H), 5.46 (br. s., 1H),5.32 (d, J = 4.0 Hz, 1H), 4.08 (s, 3H), 3.87 (s, 3H), 3.48 (br. s., 3H),2.63 (s, 3H), 1.69-1.49 (m, 6H), 1.43-1.29 (m, 2H), 1.24-1.13 (m, 1H),1.05 (d, J = 12.5 Hz, 1H). 677

382.1 1.19/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.55 (s, 1H),7.80 (s, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H),5.72-5.59 (m, 1H), 4.08 (s, 3H), 3.88 (s, 3H), 3.39 (br. s., 1H), 2.64(s, 3H), 2.56 (s, 3H).

Example 678(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl(2-methylpyrimidin-5-yl)carbamate

To a solution of Intermediate I-132 (17 mg, 0.037 mmol) in DCM (1 mL)and THF (0.5 mL) was added 2-methylpyrimidin-5-amine (8.02 mg, 0.073mmol) followed by pyridine (0.030 mL, 0.367 mmol). The mixture wasstirred at room temperature for 1 hour. The reaction was quenched with0.2 mL of MeOH. The reaction mixture was concentrated and redissolved inDMF, filtered, and purified by preparative HPLC (Method D, 25 to 100% Bin 20 minutes) to yield Example 678 (5.9 mg, 10.58 μmol, 28.8% yield):¹H NMR (500 MHz, DMSO-d₆) δ 9.97 (br. s., 1H), 8.71 (br. s., 2H),8.63-8.59 (m, 1H), 8.44 (s, 1H), 8.37 (d, J=10.7 Hz, 1H), 7.77 (s, 1H),5.26 (br. s., 1H), 4.79 (d, J=10.7 Hz, 1H), 4.57-4.44 (m, 1H), 4.05 (s,3H), 3.44 (br. s., 3H), 2.58 (s, 3H), 1.40 (d, J=6.4 Hz, 3H). LC-MS:method H, RT=1.45 min, MS (ESI) m/z: 536.2 (M+H)⁺. Analytical HPLCMethod B: 96% purity.

Examples 679 to 702

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 678 and theexamples above. If necessary, removal of silyl protecting groups wasaccomplished by treatment of the protected compound with a solution of90% MeOH, 9.9% water, and 0.1% TFA or MeOH/HCl (20/1) solution to affordthe desired compound.

LCMS RT LCMS (Min) Ex. [M + H]⁺ Method No. Structure Amine m/z H NMR 679

552.1 1.27 ¹H NMR (500 MHz, DMSO-d₆) δ 9.82 (br. s., 1H), 8.62-8.54 (m,2H), 8.40 (br. s., 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.73 (s, 1H), 5.24(br. s., 1H), 4.79 (d, J = 11.3 Hz, 1H), 4.48 (t, J = 11.6 Hz, 1H), 4.04(s, 3H), 3.45 (br. s., 1H), 2.57 (s, 3H), 2.54 (s, 3H), 1.46-1.37 (m,3H). 680

521.1 1.07 ¹H NMR (500 MHz, DMSO-d₆) δ 8.60- 8.56 (m, 1H), 8.42 (s, 1H),8.35 (d, J = 9.5 Hz, 3H), 7.75 (s, 1H), 7.43 (d, J = 5.2 Hz, 2H), 5.28(br. s., 1H), 4.78 (d, J = 10.1 Hz, 1H), 4.56-4.47 (m, 1H), 4.04 (s,3H), 2.57 (s, 3H), 1.54-1.31 (m, 3H). 681

535.1 1.06 ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (br. s., 1H), 8.62 (s, 1H),8.45 (br. s., 2H), 8.37 (d, J = 10.7 Hz, 1H), 7.77 (s, 2H), 7.16 (d, J =7.9 Hz, 1H), 5.26 (br. s., 1H), 4.75 (d, J = 9.5 Hz, 1H), 4.50 (dd, J =11.7, 6.0 Hz, 1H), 4.05 (s, 3H), 2.59 (s, 3H), 2.35 (s, 3H), 1.39 (d, J= 6.4 Hz, 3H). 682

539.1 1.27 ¹H NMR (500 MHz, DMSO-d₆) δ 10.21 (br. s., 1H), 8.60 (s, 1H),8.46-8.34 (m, 3H), 8.17 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 5.28 (br.s., 1H), 4.78 (d, J = 10.4 Hz, 1H), 4.51 (dd, J = 11.7, 5.6 Hz, 1H),4.05 (s, 3H), 3.42 (br. s., 3H), 2.58 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H).683

577.1 1.23 ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.51 (d, J = 1.7Hz, 1H), 8.43 (d, J = 10.7 Hz, 1H), 7.82 (s, 1H), 7.39- 7.33 (m, 1H),7.09-7.04 (m, 1H), 6.88 (d, J = 8.5 Hz, 1H), 5.26 (td, J = 6.3, 3.0 Hz,1H), 4.74 (dd, J = 11.7, 2.9 Hz, 1H), 4.54 (dd, J = 11.7, 6.2 Hz, 1H),4.08 (s, 3H), 2.62 (s, 3H), 1.40 (d, J = 6.6 Hz, 3H). 684

521.2 1.07 ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (s, 2H), 8.44 (s, 1H), 8.37(d, J = 10.7 Hz, 1H), 8.19 (br. s., 1H), 7.89 (br. s., 1H), 7.76 (s,1H), 7.32 (br. s., 1H), 5.28 (br. s., 1H), 4.75 (d, J = 9.8 Hz, 1H),4.52 (dd, J = 11.4, 6.0 Hz, 1H), 4.05 (s, 3H), 2.58 (s, 3H), 1.41 (d, J= 6.4 Hz, 3H). 685

I-97 582.2 1.15 ¹H NMR (400 MHz, CDCl₃) δ 8.73- 8.51 (m, 4H), 8.01 (d, J= 9.7 Hz, 1H), 7.79 (br. s., 1H), 6.64 (br. s., 1H), 5.80 (br. s., 1H),5.41 (br. s., 1H), 4.83 (br. s., 1H), 4.50 (br. s., 2H), 4.15 (s, 3H),4.00 (br. s., 2H), 2.67 (s, 3H), 1.52 (t, J = 6.1 Hz, 3H). 686

I-98 566.2 1.13 ¹H NMR (500 MHz, DMSO-d₆) δ 9.96 (br. s., 1H), 8.76-8.65(m, 3H), 8.51 (s, 2H), 8.42 (d, J = 10.7 Hz, 2H), 7.83 (s, 2H),5.75-5.64 (m, 1H), 5.27 (br. s., 1H), 4.81 (d, J = 11.6 Hz, 1H),4.58-4.46 (m, 1H), 4.07 (s, 3H), 3.77 (br. s., 2H), 2.91 (d, J = 6.7 Hz,2H), 2.61 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H). 687

I-99 631.2 1.27 ¹H NMR (500 MHz, DMSO-d₆) δ 9.69 (br. s., 1H), 8.58 (s,1H), 8.42 (s, 1H), 8.33 (d, J = 10.7 Hz, 1H), 8.20 (br. s., 1H),7.85-7.78 (m, 1H), 7.74 (s, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.72-5.59 (m,1H), 5.26 (br. s., 1H), 4.75 (d, J = 9.8 Hz, 1H), 4.56-4.43 (m, 3H),4.05 (s, 3H), 3.82-3.65 (m, 2H), 2.58 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H).688

I-103 596.1 1.26 ¹H NMR (500 MHz, DMSO-d₆) δ 9.87- 9.76 (m, 1H), 8.65(s, 1H), 8.60 (br. s., 2H), 8.48 (s, 1H), 8.41 (d, J = 10.7 Hz, 1H),7.80 (s, 1H), 5.69 (d, J = 6.4 Hz, 1H), 5.31-5.23 (m, 1H), 4.86-4.76 (m,1H), 4.53 (dd, J = 11.6, 6.1 Hz, 1H), 4.07 (s, 3H), 4.05-3.99 (m, 1H),3.93 (br. s., 1H), 3.54 (d, J = 4.9 Hz, 1H), 2.61 (s, 3H), 1.41 (d, J =6.4 Hz, 3H), 1.12 (d, J = 6.1 Hz, 3H). 689

I-107 580.2 1.20 ¹H NMR (500 MHz, DMSO-d₆) δ 9.39 (br. s., 1H), 8.23(br. s., 1H), 7.97-7.84 (m, 3H), 7.63 (d, J = 7.6 Hz, 2H), 7.34- 7.05(m, 2H), 6.57 (d, J = 9.5 Hz, 1H), 5.75 (d, J = 6.1 Hz, 1H), 2.54 (s,3H), 2.50 (br. s., 3H), 2.13 (br. s., 3H), 1.54 (d, J = 4.9 Hz, 3H). 690

579.2 1.23 ¹H NMR (500 MHz, DMSO-d₆) δ 8.65 (br. s., 2H), 8.54 (s, 1H),8.46 (d, J = 10.7 Hz, 1H), 8.05 (br. s., 1H), 8.00 (s, 1H), 7.86 (s,1H), 5.29 (br. s., 1H), 4.96 (d, J = 11.9 Hz, 1H), 4.53 (dd, J = 11.6,5.2 Hz, 1H), 4.09 (s, 3H), 2.64 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H). 691

I-109 565.1 1.00 ¹H NMR (500 MHz, DMSO-d₆) δ 9.78 (br. s., 1H), 8.65 (s,1H), 8.57-8.47 (m, 2H), 8.39 (d, J = 10.7 Hz, 1H), 7.90- 7.68 (m, 2H),7.18 (d, J = 8.5 Hz, 1H), 5.66 (br. s., 1H), 5.28 (dt, J = 6.3, 3.3 Hz,1H), 4.76 (dd, J = 11.7, 2.9 Hz, 1H), 4.53 (dd, J = 11.7, 6.3 Hz, 1H),4.07 (s, 3H), 3.68 (d, J = 5.2 Hz, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.61(s, 3H), 1.42 (d, J = 6.7 Hz, 3H). 692

I-106 596.1 1.20 ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (br. s., 1H),8.64-8.62 (m, 1H), 8.60 (br. s., 2H), 8.47 (s, 1H), 8.39 (d, J = 10.7Hz, 1H), 7.79 (s, 1H), 5.68 (br. s., 1H), 5.31-5.23 (m, 1H), 5.01 (d, J= 5.2 Hz, 1H), 4.89-4.84 (m, 1H), 4.82-4.76 (m, 1H), 4.53 (dd, J = 11.7,6.0 Hz, 2H), 4.07 (s, 3H), 2.60 (s, 3H), 1.48-1.39 (m, 3H), 1.25-1.18(m, 3H). 693

I-105 596.2 1.20 ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (br. s., 1H),8.67-8.54 (m, 2H), 8.45 (s, 2H), 8.37 (d, J = 10.7 Hz, 1H), 7.77 (s,1H), 5.68 (br. s., 1H), 5.27 (br. s., 2H), 5.00 (d, J = 5.2 Hz, 2H),4.91-4.85 (m, 1H), 4.80 (d, J = 9.5 Hz, 1H), 4.52 (dd, J = 11.6, 5.8 Hz,2H), 4.07 (s, 3H), 2.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.20 (d, J =6.4 Hz, 3H). 694

385B 551.1 1.01 ¹H NMR (500 MHz, DMSO-d₆) δ 9.87 (br. s., 1H), 8.65-8.60(m, 1H), 8.55- 8.49 (m, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.37 (d, J = 10.7Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.77 (s, 1H), 7.39 (d, J = 8.5 Hz,1H), 5.67 (br. s., 1H), 5.29 (dt, J = 6.4, 3.2 Hz, 1H), 4.76 (dd, J =11.6, 2.7 Hz, 1H), 4.54 (dd, J = 11.9, 6.1 Hz, 1H), 4.49 (s, 1H), 4.07(s, 3H), 2.60 (s, 3H), 1.51-1.35 (m, 3H). 695

I-92 593.2 1.03 ¹H NMR (500 MHz, DMSO-d₆) δ 9.72 (br. s., 1H), 8.55 (s,1H), 8.42 (br. s., 1H), 8.37 (s, 1H), 8.29 (d, J = 10.7 Hz, 1H), 7.69(s, 2H), 7.12 (d, J = 8.5 Hz, 1H), 5.25-5.15 (m, 1H), 4.68 (dd, J =11.6, 2.4 Hz, 1H), 4.59 (s, 1H), 4.46 (dd, J = 11.7, 6.3 Hz, 1H), 3.99(s, 3H), 2.52 (s, 3H), 1.35 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 2.4 Hz,6H). 696

I-94 565.2 1.02 ¹H NMR (500 MHz, DMSO-d₆) δ 8.63- 8.58 (m, 1H), 8.45 (s,1H), 8.39-8.34 (m, 1H), 8.28-8.22 (m, 1H), 7.77 (s, 1H), 7.32 (s, 1H),7.28 (d, J = 3.7 Hz, 2H), 5.72-5.61 (m, 1H), 5.33-5.26 (m, 1H), 4.78 (d,J = 9.2 Hz, 1H), 4.53 (dd, J = 11.7, 6.3 Hz, 1H), 4.07 (s, 3H), 3.68(br. s., 2H), 2.79-2.70 (m, 2H), 2.60 (s, 3H), 1.49-1.39 (m, 3H). 697

I-110 581.1 1.03 ¹H NMR (500 MHz, DMSO-d₆) δ 10.09 (br. s., 1H), 8.61(s, 1H), 8.47 (s, 1H), 8.38 (d, J = 11.0 Hz, 1H), 7.93 (d, J = 5.8 Hz,1H), 7.79 (s, 1H), 7.04 (d, J = 5.8 Hz, 1H), 6.88 (s, 1H), 5.29 (br. s.,1H), 4.80 (d, J = 11.9 Hz, 1H), 4.55- 4.50 (m, 2H), 4.22-4.14 (m, 4H),4.07 (s, 3H), 2.61 (s, 3H), 1.42 (d, J = 6.7 Hz, 3H). 698

522.1 1.03 ¹H NMR (500 MHz, DMSO-d₆) δ 10.43 (br. s., 1H), 9.16-9.11 (m,1H), 8.98 (d, J = 5.8 Hz, 1H), 8.68-8.63 (m, 1H), 8.52 (br. s., 1H),8.47-8.39 (m, 1H), 7.85 (br. s., 1H), 7.76 (br. s., 1H), 5.37-5.24 (m,1H), 4.98-4.88 (m, 1H), 4.54 (s, 1H), 4.39-4.28 (m, 1H), 4.09 (s, 3H),2.63 (s, 3H), 1.53-1.41 (m, 3H). 699

I-108 623.2 1.10 ¹H NMR (500 MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.57 (s,1H), 8.43 (s, 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.94 (d, J = 5.8 Hz, 1H),7.75 (s, 1H), 7.01 (d, J = 5.8 Hz, 1H), 6.85 (s, 1H), 5.28 (br. s., 1H),4.80 (d, J = 9.8 Hz, 1H), 4.50 (dd, J = 11.7, 5.6 Hz, 1H), 4.34-4.19 (m,2H), 4.06 (s, 3H), 3.46 (br. s., 2H), 2.59 (s, 3H), 1.76 (t, J = 7.3 Hz,2H), 1.42 (d, J = 6.4 Hz, 3H), 1.14-1.08 (m, 6H). 700

I-93 581.1 1.18 ¹H NMR (500 MHz, DMSO-d₆) δ 9.60 (br. s., 1H), 8.59 (s,1H), 8.43 (br. s., 1H), 8.34 (d, J = 10.7 Hz, 1H), 8.16 (br. s., 1H),7.75 (br. s., 2H), 6.75 (d, J = 8.9 Hz, 1H), 5.74-5.59 (m, 1H), 5.25(br. s., 1H), 4.76 (d, J = 10.1 Hz, 1H), 4.57- 4.44 (m, 1H), 4.16 (d, J= 4.3 Hz, 2H), 4.06 (s, 3H), 3.67 (br. s., 2H), 2.59 (s, 3H), 1.51-1.37(m, 3H). 701

I-104 596.1 1.26 ¹H NMR (500 MHz, DMSO-d₆) δ 9.82 (br. s., 1H),8.70-8.65 (m, 1H), 8.63- 8.55 (m, 2H), 8.51 (s, 1H), 8.43 (d, J = 11.0Hz, 1H), 7.82 (s, 1H), 5.70 (br. s., 1H), 5.27 (t, J = 6.1 Hz, 1H),4.89-4.77 (m, 2H), 4.53 (dd, J = 11.6, 5.8 Hz, 1H), 4.08 (s, 3H),4.03-3.89 (m, 1H), 3.58-3.34 (m, 1H), 2.62 (s, 3H), 1.41 (d, J = 6.4 Hz,3H), 1.11 (d, J = 5.8 Hz, 3H). 702

I-100 624.2 1.30 ¹H NMR (500 MHz, DMSO-d₆) δ 9.79 (br. s., 1H), 8.69 (s,1H), 8.59 (br. s., 2H), 8.53 (s, 1H), 8.44 (d, J = 10.7 Hz, 1H), 7.84(s, 1H), 5.25 (br. s., 1H), 4.85 (br. s., 1H), 4.58-4.48 (m, 1H), 4.38(s, 1H), 4.30 (d, J = 7.6 Hz, 2H), 4.09 (s, 3H), 3.43-3.33 (m, 2H), 2.63(s, 3H), 1.41 (d, J = 6.7 Hz, 3H), 1.14 (s, 6H).

Example 708(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbamate

To a solution of Intermediate I-134 (17 mg, 0.036 mmol) in DCM (1 mL)and THF (0.5 mL), was added 6-aminobenzo[d]oxazol-2(3H)-one (10.70 mg,0.071 mmol) followed by pyridine (0.029 mL, 0.356 mmol). The mixture wasstirred at room temperature for 1 hour. The reaction was quenched with0.2 mL of MeOH. The reaction mixture was concentrated and redissolved inDMF, filtered, and purified by preparative HPLC (Method D, 40 to 80% Bin 20 minutes) to yield Example 708 (6 mg, 9.96 μmol, 27.9% yield): ¹HNMR (500 MHz, DMSO-d₆) δ 9.56 (br. s., 1H), 8.53 (s, 1H), 8.44 (s, 1H),8.35 (d, J=10.4 Hz, 1H), 7.75 (s, 1H), 7.39 (br. s., 1H), 7.09 (br. s.,1H), 6.91 (d, J=7.6 Hz, 1H), 5.64 (d, J=6.4 Hz, 1H), 5.13 (d, J=6.4 Hz,1H), 4.06 (s, 3H), 3.54-3.38 (m, 1H), 2.59 (s, 3H), 1.45 (d, J=6.4 Hz,3H), 1.40-1.35 (m, 3H). LC-MS: method H, RT=1.28 min, MS (ESI) m/z:591.1 (M+H)⁺. Analytical HPLC Method B: 98% purity.

Examples 709 to 731

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 708 and theexamples above. If necessary, removal of silyl protecting groups wasaccomplished by treatment of the protected compound with a solution of90% MeOH, 9.9% water, and 0.1% TFA or MeOH/HCl (20/1) solution to affordthe desired compound.

LCMS LCMS RT [M + (Min) Ex. H]⁺ Method No. Structure Amine m/z H NMR 709

535.2 1.01 ¹H NMR (500 MHz, DMSO-d₆) δ 9.81 (br. s., 1H), 8.61- 8.50 (m,2H), 8.39 (br. s., 1H), 8.31 (d, J = 10.7 Hz, 1H), 8.16 (br. s., 1H),7.87 (br. s., 1H), 7.72 (br. s., 1H), 7.30 (br. s., 1H), 5.62 (d, J =5.2 Hz, 1H), 5.16 (d, J = 6.1 Hz, 1H), 4.05 (s, 3H), 3.56 (br. s., 3H),1.45 (d, J = 5.8 Hz, 3H), 1.39 (d, J = 5.8 Hz, 3H). 710

549.1 1.11 ¹H NMR (500 MHz, DMSO-d₆) δ 9.76 (br. s., 1H), 8.60 (s, 1H),8.46 (br. s., 2H), 8.38 (d, J = 10.7 Hz, 1H), 7.78 (br. s., 2H), 7.21(br. s., 1H), 5.66 (d, J = 6.7 Hz, 1H), 5.14 (d, J = 6.1 Hz, 1H), 4.07(s, 3H), 2.60 (s, 3H), 2.35 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H), 1.39 (d,J = 6.4 Hz, 3H). 711

566.0 1.31 ¹H NMR (500 MHz, DMSO-d₆) δ 9.70 (br. s., 1H), 8.60 (d, J =9.2 Hz, 3H), 8.48 (s, 1H), 8.40 (d, J = 10.4 Hz, 1H), 7.80 (s, 1H), 5.73(d, J = 5.2 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H), 4.08 (s, 3H), 3.79 (s,3H), 2.61 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H).712

I-107 594.2 1.18 ¹H NMR (500 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.91 (br.s., 2H), 8.49-8.41 (m, 2H), 8.37 (d, J = 11.0 Hz, 1H), 7.75 (s, 1H),5.82 (d, J = 6.7 Hz, 1H), 5.14 (d, J = 5.2 Hz, 1H), 4.07 (s, 3H), 3.83(s, 3H), 2.58 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 6.4 Hz,3H). 713

535.2 1.01 ¹H NMR (500 MHz, DMSO-d₆) δ 10.04 (s, 1H), 8.50 (s, 1H), 8.39(s, 1H), 8.34-8.29 (m, 3H), 7.72 (s, 1H), 7.39 (d, J = 5.2 Hz, 2H), 5.66(d, J = 6.7 Hz, 1H), 5.16 (d, J = 6.7 Hz, 1H), 4.05 (s, 3H), 2.56 (s,3H), 1.45 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H). 714

553.2 1.25 ¹H NMR (500 MHz, DMSO-d₆) δ 10.07 (br. s., 1H), 8.51 (s, 1H),8.40 (s, 1H), 8.36 (br. s., 1H), 8.32 (d, J = 10.7 Hz, 1H), 8.13 (br.s., 1H), 7.83-7.76 (m, 1H), 7.72 (s, 1H), 5.67 (d, J = 6.4 Hz, 1H), 5.15(d, J = 6.4 Hz, 1H), 4.05 (s, 3H), 2.58-2.56 (m, 3H), 1.44 (d, J = 6.1Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H). 715

593.2 1.21 ¹H NMR (500 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.54 (br. s., 1H),8.44 (s, 1H), 8.41 (s, 1H), 8.33 (d, J = 10.7 Hz, 1H), 8.00 (br. s.,1H), 7.93 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 5.81 (d, J = 6.4 Hz, 1H),5.11 (d, J = 6.4 Hz, 1H), 4.06 (s, 3H), 3.77 (s, 3H), 2.58 (br. s., 3H),1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H). 716

536.3 1.23 ¹H NMR (500 MHz, DMSO-d₆) δ 10.12-9.93 (m, 1H), 8.83 (br. s.,2H), 8.79 (s, 1H), 8.67 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.44 (d, J =10.7 Hz, 1H), 7.85 (s, 1H), 5.70 (dd, J = 6.7, 2.6 Hz, 1H), 5.16 (dd, J= 6.6, 2.5 Hz, 1H), 4.09 (s, 3H), 2.63 (s, 3H), 1.45 (d, J = 6.6 Hz,3H), 1.40 (d, J = 6.6 Hz, 3H). 717

I-94  579.3 1.00 1H NMR (500 MHz, DMSO-d₆) δ 10.00 (s, 1H), 8.60 (s,1H), 8.49 (s, 1H), 8.40 (d, J = 11.0 Hz, 1H), 8.24 (d, J = 5.5 Hz, 1H),7.80 (s, 1H), 7.29 (br. s., 2H), 5.67 (d, J = 6.4 Hz, 1H), 5.16 (d, J =6.7 Hz, 1H), 4.08 (s, 3H), 3.64 (t, J = 6.6 Hz, 2H), 2.72 (t, J = 6.7Hz, 2H), 2.61 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.4 Hz,3H). 718

I-92  607.2 1.06 ¹H NMR (500 MHz, DMSO-d₆) δ 9.64 (br. s., 1H), 8.54 (s,1H), 8.40 (s, 2H), 8.29 (d, J = 10.7 Hz, 1H), 7.74 (s, 2H), 7.22-7.13(m, 1H), 5.65 (dd, J = 6.7, 2.4 Hz, 1H), 5.12 (dd, J = 6.7, 2.4 Hz, 1H),4.05 (s, 3H), 3.71-3.70 (m, 1H), 2.67 (d, J = 9.2 Hz, 2H), 2.57 (s, 3H),1.43 (d, J = 6.7 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 8.9 Hz,6H). 719

I-110 595.1 1.07 ¹H NMR (500 MHz, DMSO-d₆) δ 9.93 (s, 1H), 8.55 (s, 1H),8.46 (s, 1H), 8.36 (d, J = 10.7 Hz, 1H), 7.89 (d, J = 5.5 Hz, 1H), 7.77(s, 1H), 7.00 (d, J = 5.5 Hz, 1H), 6.81 (s, 1H), 5.68 (dd, J = 6.6, 2.3Hz, 1H), 5.14 (dd, J = 6.7, 2.1 Hz, 1H), 4.19-4.09 (m, 3H), 4.07 (s,3H), 3.65-3.58 (m, 1H), 3.46 (br. s., 1H), 2.60 (s, 3H), 1.44 (d, J =6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H). 720

I-109 579.1 1.04 MS (ESI) m/z: 579.1 (M + H)⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 9.67 (br. s., 1H), 8.58 (s, 1H), 8.44 (s, 2H), 8.33 (d, J = 10.7 Hz,1H), 7.76 (s, 2H), 7.16 (d, J = 7.9 Hz, 1H), 5.62 (dd, J = 6.4, 2.4 Hz,1H), 5.14 (dd, J = 6.4, 2.4 Hz, 1H), 4.06 (s, 3H), 3.65 (t, J = 6.9 Hz,1H), 3.48 (br. s., 1H), 2.76 (d, J = 4.0 Hz, 2H), 2.59 (s, 3H), 1.44 (d,J = 6.4 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H). 721

I-97  596.1 1.21 ¹H NMR (500 MHz, DMSO-d₆) δ 9.71 (br. s., 1H), 8.62(br. s., 1H), 8.50 (s, 1H), 8.40 (d, J = 10.7 Hz, 1H), 7.82 (s, 1H),5.75 (d, J = 6.4 Hz, 1H), 5.17 (d, J = 6.7 Hz, 1H), 4.96 (t, J = 5.5 Hz,1H), 4.28-4.16 (m, 2H), 4.12 (s, 3H), 3.72 (d, J = 5.2 Hz, 2H), 2.65 (s,3H), 1.49 (d, J = 6.4 Hz, 3H), 1.43 (d, J = 6.7 Hz, 3H). 722

I-106 610.1 1.24 ¹H NMR (500 MHz, DMSO-d₆) δ 9.78-9.71 (m, 1H),8.70-8.60 (m, 2H), 8.52 (s, 1H), 8.43 (d, J = 10.4 Hz, 1H), 7.84 (s,1H), 5.73 (dd, J = 6.4, 2.4 Hz, 1H), 5.18 (dd, J = 6.6, 2.3 Hz, 1H),5.02 (br. s., 1H), 4.93-4.86 (m, 1H), 4.13 (s, 3H), 3.65-3.38 (m, 3H),2.66 (s, 3H), 1.49 (d, J = 6.1 Hz, 3H), 1.43 (d, J = 6.7 Hz, 3H). 723

I-94  565.1 1.05 ¹H NMR (500 MHz, DMSO-d₆) δ 9.82-9.74 (m, 1H), 8.63 (s,1H), 8.48 (s, 1H), 8.53-8.46 (m, 2H), 8.39 (d, J = 11.0 Hz, 1H),7.92-7.83 (m, 1H), 7.80 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 5.64 (dd, J =6.6, 2.6 Hz, 1H), 5.16 (dd, J = 6.6, 2.3 Hz, 1H), 4.47 (s, 2H), 4.08 (s,3H), 2.61 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H).724

I-105 610.1 1.23 ¹H NMR (500 MHz, DMSO-d₆) δ 9.68-9.57 (m, 1H), 8.57 (s,1H), 8.52 (br. s., 1H), 8.43 (s, 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.75(s, 1H), 5.65 (dd, J = 6.7, 2.4 Hz, 1H), 5.08 (d, J = 4.0 Hz, 1H), 4.91(d, J = 5.5 Hz, 1H), 4.80 (t, J = 5.6 Hz, 1H), 4.03 (s, 3H), 3.54-3.38(m, 3H), 2.56 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.7 Hz,3H), 1.10 (d, J = 6.1 Hz, 3H). 725

I-93  595.2 1.22 ¹H NMR (500 MHz, DMSO-d₆) δ 9.42 (br. s., 1H), 8.52(br. s., 1H), 8.40 (br. s., 1H), 8.34-8.24 (m, 1H), 8.14- 8.01 (m, 1H),7.73 (br. s., 2H), 6.80-6.59 (m, 1H), 5.66 (br. s., 1H), 5.09 (d, J =6.1 Hz, 1H), 4.92 (s, 1H), 4.15- 4.08 (m, 1H), 4.05 (s, 3H), 3.72-3.57(m, 4H), 2.59-2.55 (m, 3H), 1.42 (d, J = 6.1 Hz, 3H), 1.35 (d, J = 6.4Hz, 3H). 726

I-99  645.2 1.30 ¹H NMR (500 MHz, DMSO-d₆) δ 9.57 (br. s., 1H), 8.54 (s,1H), 8.42 (s, 1H), 8.31 (d, J = 10.4 Hz, 1H), 8.17 (br. s., 1H), 7.85(br. s., 1H), 7.75 (s, 1H), 6.88 (br. s., 1H), 5.79 (t, J = 6.1 Hz, 1H),5.71 (d, J = 5.8 Hz, 1H), 5.17 (d, J = 5.8 Hz, 1H), 4.60-4.39 (m, 2H),4.10 (s, 3H), 3.77 (br. s., 2H), 2.61 (s, 3H), 1.49 (d, J = 6.4 Hz, 3H),1.42 (d, J = 6.4 Hz, 3H). 727

I-108 637.2 1.13 ¹H NMR (500 MHz, DMSO-d₆) δ 9.90 (s, 1H), 8.54 (s, 1H),8.45 (s, 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.90 (d, J = 5.2 Hz, 1H), 7.77(s, 1H), 6.99 (d, J = 5.2 Hz, 1H), 6.76 (s, 1H), 5.70 (d, J = 4.9 Hz,1H), 5.13 (d, J = 6.4 Hz, 1H), 4.27-4.13 (m, 2H), 4.06 (s, 3H), 3.48 (s,1H), 2.59 (s, 3H), 2.52 (br. s., 6H), 1.72 (t, J = 6.4 Hz, 2H), 1.44 (d,J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H). 728

I-103 610.2 1.29 ¹H NMR (500 MHz, DMSO-d₆) δ 9.72-9.62 (m, 1H), 8.63(br. s., 1H), 8.57 (br. s., 2H), 8.50 (s, 1H), 8.41 (d, J = 10.4 Hz,1H), 7.81 (s, 1H), 5.71 (d, J = 6.7 Hz, 1H), 5.12 (dd, J = 6.4, 2.1 Hz,1H), 4.97 (d, J = 5.5 Hz, 1H), 4.84 (d, J = 4.9 Hz, 1H), 4.08 (s, 3H),4.06-3.96 (m, 1H), 3.94-3.89 (m, 2H), 2.62 (s, 3H), 1.44 (d, J = 6.4 Hz,3H), 1.38 (d, J = 6.7 Hz, 3H), 1.10 (t, J = 5.8 Hz, 3H). 729

I-104 610.2 1.29 ¹H NMR (500 MHz, DMSO-d₆) δ 9.72-9.65 (m, 1H), 8.64(br. s., 1H), 8.57 (br. s., 2H), 8.51 (s, 1H), 8.41 (d, J = 10.7 Hz,1H), 7.82 (s, 1H), 5.71 (d, J = 6.4 Hz, 1H), 5.16-5.09 (m, 1H), 4.84 (d,J = 4.9 Hz, 1H), 4.08 (s, 3H), 4.06-3.97 (m, 1H), 3.91 (s, 2H), 2.62 (s,3H), 1.44 (d, J = 6.1 Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H), 1.10 (s, 3H).730

I-100 638.2 1.32 ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.56 (br. s.,2H), 8.50 (s, 1H), 8.40 (d, J = 10.7 Hz, 1H), 7.81 (s, 1H), 5.73 (d, J =4.9 Hz, 1H), 5.11 (dd, J = 6.4, 1.8 Hz, 1H), 4.34-4.16 (m, 2H), 4.08 (s,3H), 2.61 (s, 3H), 1.78 (t, J = 7.3 Hz, 2H), 1.43 (d, J = 6.4 Hz, 3H),1.38 (d, J = 6.7 Hz, 3H), 1.13 (d, J = 2.7 Hz, 6H). 731

550.2 1.23 ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (br. s., 2H), 8.62 (s, 1H),8.49 (s, 1H), 8.40 (d, J = 11.0 Hz, 1H), 7.81 (s, 1H), 5.69 (d, J = 6.4Hz, 1H), 5.12 (d, J = 6.4 Hz, 1H), 4.07 (s, 3H), 2.60 (s, 3H), 2.46 (s,3H), 1.43 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H).

Example 733(R)-1-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ylpyridin-3-ylcarbamate

To a solution of Intermediate I-138 (10 mg, 0.022 mmol) in DCM (1 mL)and THF (0.5 mL) was added pyridin-3-amine (7.18 mg, 0.076 mmol)followed by DIEA (0.038 mL, 0.218 mmol). The mixture was stirred at roomtemperature for 1 h. The reaction was quenched with 0.2 mL of MeOH. Thereaction mixture was concentrated, redissolved in DMF, filtered, andpurified by preparative HPLC (Method D, 25 to 100% B in 15 minutes) toyield Example 733 (3.5 mg, 6.57 μmol, 30.2% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 8.70 (s, 1H), 8.62 (br. s., 1H), 8.54 (s, 1H), 8.19 (br. s.,1H), 7.89 (br. s., 1H), 7.82 (s, 1H), 7.30 (d, J=7.9 Hz, 1H), 6.90 (s,1H), 5.24 (br. s., 1H), 4.65-4.41 (m, 2H), 4.08 (s, 3H), 2.72 (s, 3H),2.63 (s, 3H), 1.39 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.07 min, MS(ESI) m/z: 517.2 (M+H)⁺. Analytical HPLC Method B: 97% purity.

Examples 734 to 740

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 733 and theexamples above

LCMS LCMS RT [M + (Min) Ex. H]⁺ Method No. Structure Amine m/z H NMR 734

549.2 1.36 ¹H NMR (500 MHz, DMSO-d₆) δ 9.88 (br. s., 1H), 8.68 (s, 1H),8.53 (s, 1H), 8.05 (br. s., 1H), 7.81 (s, 1H), 6.90 (s, 1H), 5.22 (br.s., 1H), 4.68-4.38 (m, 2H), 4.08 (s, 3H), 2.72 (s, 3H), 2.63 (s, 3H),2.18 (s, 3H), 1.38 (d, J = 6.1 Hz, 4H). 735

542.2 1.30 ¹H NMR (500 MHz, DMSO-d₆) δ 10.30 (br. s., 1H), 8.81 (br. s.,1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 8.26 (br. s., 1H), 7.80(s, 1H), 6.89 (s, 1H), 5.26 (br. s., 1H), 4.74-4.34 (m, 2H), 4.07 (s,3H), 2.71 (s, 3H), 2.62 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H). 736

553.1 1.35 ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (br. s., 2H), 8.59 (s, 1H),8.44 (s, 1H), 7.73 (s, 1H), 6.85 (s, 1H), 5.22 (br. s., 1H), 4.68 (d, J= 9.5 Hz, 1H), 4.38 (dd, J = 11.9, 6.1 Hz, 1H), 4.04 (s, 3H), 2.67 (s,3H), 2.58 (s, 3H), 1.39 (d, J = 6.7 Hz, 3H). 737

532.2 1.25 ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (br. s., 2H), 8.59 (s, 1H),8.43 (s, 1H), 7.73 (s, 1H), 6.84 (s, 1H), 5.22 (dd, J = 6.4, 3.4 Hz,1H), 4.61 (dd, J = 11.7, 2.6 Hz, 1H), 4.39 (dd, J = 11.7, 6.3 Hz, 1H),4.04 (s, 3H), 2.66 (s, 3H), 2.58 (s, 3H), 2.51 (br. s., 3H), 1.38 (d, J= 6.4 Hz, 3H). 738

548.2 1.30 ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.61 (br. s., 2H),8.52 (s, 1H), 7.80 (s, 1H), 6.89 (s, 1H), 5.19 (br. s., 1H), 4.66 (d, J= 9.5 Hz, 1H), 4.39 (dd, J = 11.7, 6.0 Hz, 1H), 4 06 (s, 3H), 3.86-3.79(m, 3H), 2.70 (s, 3H), 2.62 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H). 740

530.2 1.12 ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (br. s., 1H), 8.62-8.57 (m,1H), 8.55 (s, 1H), 8.42 (s, 1H), 8.18 (br. s., 1H), 7.88 (br. s., 1H),7.72 (s, 1H), 7.38- 7.22 (m, 1H), 6.80 (s, 1H), 5.56-5.46 (m, 1H), 5.10(dd, J = 6.4, 2.4 Hz, 1H), 4.04 (s, 3H), 2.66 (s, 3H), 2.58 (s, 3H),1.37 (dd, J = 11.6, 6.4 Hz, 6H).

Example 741(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl(6-((2-hydroxy-2-methylpropyl)carbamoyl)pyridin-3-yl)carbamate

To a suspension of Example 689 (0.012 g, 0.021 mmol) in THF (0.207 ml)was added 1-amino-2-methylpropan-2-ol (0.029 ml, 0.622 mmol) followed bymagnesium chloride (0.020 g, 0.207 mmol). The reaction vial was sealedand heated to 65° C. overnight. The reaction mixture was diluted withEtOAc and filtered through Celite. The reaction mixture wasconcentrated, redissolved in DMF, filtered, and purified by preparativeHPLC (Method D, 50 to 100% B in 21 minutes) to yield Example 741 (0.0011g, 1.713 mol, 8.26% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 10.15 (br. s.,1H), 8.60 (br. s., 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.35 (d, J=11.0 Hz,1H), 8.26 (br. s., 1H), 8.04 (d, J=7.9 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H),7.78 (s, 1H), 5.28 (br. s., 1H), 4.89 (d, J=10.1 Hz, 1H), 4.50 (dd,J=11.7, 5.6 Hz, 1H), 4.06 (s, 3H), 3.23 (dd, J=11.1, 6.3 Hz, 2H), 2.59(s, 3H), 1.43 (d, J=6.4 Hz, 3H), 1.08 (d, J=5.8 Hz, 6H). LC-MS: methodH, RT=1.23 min, MS (ESI) m/z: 636.2 (M+H)⁺. Analytical HPLC Method B:99% purity.

Examples 742 to 749

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 741 and theexamples above.

LCMS LCMS [M + RT Ex. H]⁺ (Min)/ No. Structure ester m/z Method NMR 742

689 632.2 2.17/B ¹H NMR (500 MHz, DMSO-d₆) δ 10.16 (br. s., 2H), 8.61(br. s., 2H), 8.50 (br. s., 1H), 8.41 (d, J = 9.8 Hz, 1H), 8.03 (br. s.,1H), 7.95 (d, J = 8.5 Hz, 1H), 7.82 (br. s., 1H), 5.83- 5.67 (m, 1H),5.29 (br. s., 2H), 4.95-4.83 (m, 3H), 4.53 (br. s., 2H), 4.08 (br. s.,3H), 3.38 (br. s., 3H), 2.62 (br. s., 3H), 1.85-1.66 (m, 6H). 743

689 648.2 2.25/B ¹H NMR (500 MHz, DMSO-d₆) δ 10.11 (d, J = 12.2 Hz, 1H),8.58 (br. s., 2H), 8.42 (br. s., 1H), 8.33 (d, J = 10.1 Hz, 1H), 7.99(br. s., 1H), 7.74 (br. s., 1H), 7.51 (t, J = 10.2 Hz, 1H), 5.31 (br.s., 1H), 5.06 (br. s., 1H), 4.78 (d, J = 10.1 Hz, 2H), 4.06 (s, 3H),3.51 (s, 2H), 3.14 (br. s., 2H), 3.01-2.91 (m, 2H), 2.58 (s, 3H),1.92-1.72 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H). 744

689 634.2 2.20/B ¹H NMR (500 MHz, DMSO-d₆) δ 10.15-10.04 (m, 1H), 8.56(d, J = 10.1 Hz, 2H), 8.42 (br. s., 1H), 8.33 (d, J = 10.4 Hz, 1H), 8.02(br. s., 1H), 7.75 (br. s., 2H), 5.30 (br. s., 1H), 5.09-4.97 (m, 1H),4.92-4.74 (m, 1H), 4.52 (br. s., 1H), 4.28 (br. s., 1H), 4.05 (s, 3H),3.80-3.67 (m, 1H), 3.52-3.36 (m, 2H), 2.58 (br. s., 3H), 1.95-1.84 (m,1H), 1.77 (br. s., 2H), 1.43 (d, J = 6.1 Hz, 3H). 745

689 634.2 2.20/B ¹H NMR (500 MHz, DMSO-d₆) δ 10.15-10.04 (m, 1H), 8.56(d, J = 10.1 Hz, 2H), 8.42 (br. s., 1H), 8.33 (d, J = 10.4 Hz, 1H), 8.02(br. s., 1H), 7.75 (br. s., 2H), 5.30 (br. s., 1H), 5.09-4.97 (m, 1H),4.92-4.74 (m, 1H), 4.52 (br. s., 1H), 4.28 (br. s., 1H), 4.05 (s, 3H),3.80-3.67 (m, 1H), 3.52-3.36 (m, 2H), 2.58 (br. s., 3H), 1.95-1.84 (m,1H), 1.77 (br. s., 2H), 1.43 (d, J = 6.1 Hz, 3H). 746

689 648.2 2.19/B ¹H NMR (500 MHz, DMSO-d₆) δ 10.11 (br. s., 2H), 8.63-8.53 (m, 2H), 8.45 (s, 1H), 8.36 (d, J = 10.7 Hz, 1H), 7.98 (br. s.,1H), 7.77 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 5.31 (br. s., 1H),4.87-4.75 (m, 2H), 4.61-4.48 (m, 1H), 4.06 (s, 3H), 4.01 (br. s., 1H),3.72 (br. s., 1H), 3.60 (br. s., 1H), 3.22- 3.10 (m, 2H), 2.60 (s, 3H),1.79 (br. s., 1H), 1.67 (br. s., 1H), 1.43 (d, J = 6.1 Hz, 3H),1.40-1.24 (m, 2H). 747

689 622.1 1.17/H ¹H NMR (500 MHz, DMSO-d₆) δ 10.16 (br. s., 2H), 8.62(br. s., 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.41-8.34 (m, 2H), 8.03 (br.s., 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 5.29 (br. s., 1H), 4.89(d, J = 10.1 Hz, 1H), 4.52 (dd, J = 11.7, 5.3 Hz, 1H), 4.07 (s, 3H),3.75 (br. s., 1H), 3.53 (s, 1H), 3.32- 3.25 (m, 1H), 3.18-3.10 (m, 1H),2.61 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.10-0.99 (m, 3H). 748

689 622.2 1.17/H ¹H NMR (500 MHz, DMSO-d₆) δ 10.17 (br. s., 2H), 8.63(br. s., 1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.43-8.33 (m, 2H), 8.03 (br.s., 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 5.29 (br. s., 1H), 4.88(d, J = 10.1 Hz, 1H), 4.52 (dd, J = 11.3, 5.5 Hz, 1H), 4.07 (s, 3H),3.77 (br. s., 1H), 3.50-3.44 (m, 1H), 3.30 (br. s., 1H), 3.13 (d, J =7.0 Hz, 1H), 2.61 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 5.8Hz, 3H). 749

690 565.1 1.10/H ¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (br. s., 2H), 8.58 (s,1H), 8.43 (s, 1H), 8.36 (d, J = 10.8 Hz, 1H), 8.19-8.01 (m, 2H), 7.75(s, 1H), 7.65 (br. s., 1H), 5.35-5.26 (m, 1H), 4.84 (d, J = 9.8 Hz, 1H),4.59-4.48 (m, 1H), 4.05 (s, 3H), 2.58 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H).

Example 750(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(6-(((S)-2-hydroxypropyl)carbamoyl)pyridin-3-yl)carbamate

To a suspension of Example 715 (0.030 g, 0.051 mmol) in THF (0.506 ml)was added (S)-1-aminopropan-2-ol (0.114 g, 1.519 mmol) followed bymagnesium chloride (0.047 g, 0.510 mmol). The reaction vial was sealedand heated to 65° C. overnight. The reaction mixture was diluted withEtOAc and filtered through Celite. The reaction mixture wasconcentrated, redissolved in DMF, filtered, and purified by preparativeHPLC (Method D, 35 to 100% B in 20 minutes) to yield Example 750 (0.0129g, 0.020 mmol, 40.1% yield ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br. s.,1H), 8.51 (d, J=8.2 Hz, 1H), 8.41 (s, 2H), 8.31 (d, J=10.7 Hz, 2H), 7.99(br. s., 1H), 7.89 (t, J=7.3 Hz, 1H), 7.73 (s, 1H), 5.77 (d, J=6.7 Hz,1H), 5.12 (d, J=6.4 Hz, 1H), 4.91 (s, 1H), 4.05 (s, 3H), 3.77-3.69 (m,1H), 3.38-2.96 (m, 2H), 2.57 (s, 3H), 1.44 (d, J=6.4 Hz, 3H), 1.38 (d,J=6.4 Hz, 3H), 1.08-0.98 (m, 3H). LC-MS: method H, RT=1.23 min,): MS(ESI) m/z: 636.1 (M+H)⁺. Analytical HPLC Method B: 100% purity.

Examples 751 to 761

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 741 and theexamples above.

LCMS LCMS RT Ex. [M + H]⁺ (Min)/ No. Structure ester m/z Method NMR 751

712 650.2 2.37/B ¹H NMR (500 MHz, DMSO-d₆) δ 10.23-10.17 (m, 1H), 8.90(br. s., 2H), 8.48 (s, 1H), 8.43 (s, 1H), 8.37-8.30 (m, 2H), 7.75 (s,1H), 5.78 (dd, J = 6.6, 2.3 Hz, 1H), 5.22-5.08 (m, 1H), 4.72 (s, 1H),4.05 (s, 3H), 3.51-3.45 (m, 2H), 3.30-3.14 (m, 2H), 2.58 (s, 3H), 1.45(d, J = 6.7 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 10.4 Hz,6H). 752

712 637.2 1.14/H ¹H NMR (500 MHz, DMSO-d₆) δ 10.16 (br. s., 1H), 8.87(br. s., 2H), 8.47 (s, 2H), 8.43 (s, 1H), 8.34 (d, J = 11.0 Hz, 1H),7.75 (s, 1H), 5.78 (d, J = 6.7 Hz, 1H), 5.13 (d, J = 6.7 Hz, 1H), 4.86(d, J = 4.9 Hz, 1H), 4.04 (s, 3H), 3.81-3.71 (m, 1H), 3.47 (s, 3H),3.31-3.22 (m, 1H), 3.16-3.06 (m, 1H), 2.57 (s, 3H), 1.43 (d, J = 6.4 Hz,2H), 1.38 (d, J = 6.4 Hz, 2H), 1.03 (d, J = 6.1 Hz, 3H). 753

712 637.2 1.14/H ¹H NMR (500 MHz, DMSO-d₆) δ 10.16 (br. s., 1H), 8.87(br. s., 2H), 8.47 (s, 2H), 8.43 (s, 1H), 8.34 (d, J = 11.0 Hz, 1H),7.75 (s, 1H), 5.78 (d, J = 6.7 Hz, 1H), 5.13 (d, J = 6.7 Hz, 1H), 4.86(d, J = 4.9 Hz, 1H), 4.04 (s, 3H), 3.81-3.71 (m, 1H), 3.47 (s, 3H),3.31-3.22 (m, 1H), 3.16-3.06 (m, 1H), 2.57 (s, 3H), 1.43 (d, J = 6.4 Hz,2H), 1.38 (d, J = 6.4 Hz, 2H), 1.03 (d, J = 6.1 Hz, 3H). 754

715 578.2 1.23/H ¹H NMR (500 MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.60 (br.s., 1H), 8.53 (s, 1H), 8.45 (s, 1H), 8.38 (d, J = 10.8 Hz, 1H),8.02-7.97 (m, 1H), 7.95-7.88 (m, 2H), 7.76 (s, 1H), 7.42 (br. s., 1H),5.69 (dd, J = 6.4, 2.4 Hz, 1H), 5.20-5.11 (m, 1H), 4.06 (s, 3H), 2.59(s, 3H), 1.45 (d, J = 6.4 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H). 755

712 579.0 1.14/H ¹H NMR (500 MHz, DMSO-d₆) δ 10.27 (br. s., 1H), 8.92(br. s., 2H), 8.59 (s, 1H), 8.48 (s, 1H), 8.41 (d, J = 10.8 Hz, 1H),8.06 (br. s., 1H), 7.79 (s, 1H), 7.64 (br. s., 1H), 5.73 (d, J = 6.4 Hz,1H), 5.18 (d, J = 4.4 Hz, 1H), 4.07 (s, 3H), 2.60 (s, 3H), 1.46 (d, J =6.7 Hz, 3H), 1.41 (d, J = 6.7 Hz, 3H). 756

715 678.2 2.56/B ¹H NMR (500MHz, DMSO-d₆) δ 10.01 (br. s., 1H), 8.64 (s,1H), 8.59-8.53 (m, 1H), 8.51 (s, 1H), 8.41 (d, J = 11.0 Hz, 1H), 8.05-7.93 (m, 1H), 7.82 (s, 1H), 7.59- 7.52 (m, 1H), 5.67 (br. s., 1H), 5.17(d, J = 6.1 Hz, 1H), 4.36- 4.15 (m, 1H), 4.08 (s, 3H), 4.05- 3.99 (m,1H), 3.91 (s, 2H), 3.75 (br. s., 2H), 3.66-3.31 (m, 3H), 3.33-2.97 (m,1H), 2.62 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 6.4 Hz, 3H).757

715 648.2 2.41/B ¹H NMR (500 MHz, DMSO-d₆) δ 9.99-9.88 (m, 1H),8.52-8.48 (m, 1H), 8.42 (br. s., 1H), 8.38- 8.28 (m, 2H), 8.12-7.87 (m,1H), 7.74 (br. s., 1H), 7.69 (d, J = 7.9 Hz, 1H), 5.81-5.65 (m, 1H),5.14 (br. s., 1H), 5.05-4.92 (m, 1H), 4.24 (br. s., 1H), 4.05 (s, 3H),3.58 (d, J = 5.8 Hz, 3H), 3.51- 3.32 (m, 1H), 2.58 (s, 3H), 1.93- 1.65(m, 2H), 1.45 (br. s., 3H), 1.39 (d, J = 6.1 Hz, 3H). 758

715 662.2 2.47/B ¹H NMR (500 MHz, DMSO-d₆) δ 9.96 (d, J = 18.9 Hz, 1H),8.54 (br. s., 2H), 8.41 (br. s., 1H), 8.32 (d, J = 10.7 Hz, 1H), 7.96(br. s., 1H), 7.74 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 5.67 (br. s., 2H),5.18-5.09 (m, 2H), 4.90 (d, J = 4.9 Hz, 1H), 4.05 (s, 3H), 3.84 (br. s.,1H), 3.47 (br. s., 1H), 3.14 (br. s., 1H), 2.90 (s, 1H), 2.82-2.64 (m,1H), 2.56 (s, 3H), 1.90-1.70 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.39 (d,J = 6.4 Hz, 3H). 759

715 662.0 2.97/B ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br. s., 1H), 8.53 (s,2H), 8.40 (s, 1H), 8.30 (d, J = 10.7 Hz, 1H), 8.04-7.90 (m, 1H), 7.72(s, 1H), 7.49 (br. s., 1H), 5.67 (br. s., 1H), 5.15 (d, J = 6.4 Hz, 1H),4.90 (br. s., 1H), 4.04 (s, 3H), 3.74-3.55 (m, 4H), 3.24-2.95 (m, 2H),2.57 (br. s., 3H), 1.78 (br. s., 1H), 1.68-1.54 (m, 1H), 1.44 (d, J =6.1 Hz, 3H), 1.39 (d, J = 6.1 Hz, 3H), 1.27 (br. s., 1H). 760

715 648.0 2.98/B ¹H NMR (500 MHz, DMSO-d₆) δ 9.99-9.88 (m, 1H),8.52-8.48 (m, 1H), 8.42 (br. s., 1H), 8.38- 8.28 (m, 2H), 8.12-7.87 (m,1H), 7.74 (br. s., 1H), 7.69 (d, J = 7.9 Hz, 1H), 5.81-5.65 (m, 1H),5.14 (br. s., 1H), 5.05-4.92 (m, 1H), 4.24 (br. s., 1H), 4.05 (s, 3H),3.58 (d, J = 5.8 Hz, 3H), 3.51-3.32 (m, 1H), 2.58 (s, 3H), 1.93- 1.65(m, 2H), 1.45 (br. s., 3H), 1.39 (d, J = 6.1 Hz, 3H). 761

712 676.0 3.43/B ¹H NMR (500 MHz, DMSO-d₆) δ 9.98 (br. s., 1H), 8.51 (d,J = 7.0 Hz, 2H), 8.45 (d, J = 11.6 Hz, 2H), 8.33 (d, J = 10.7 Hz, 1H),7.99 (br. s., 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 5.76 (d, J =6.4 Hz, 1H), 5.14 (br. s., 1H), 4.83 (br. s., 1H), 4.06 (s, 3H), 3.36(d, J = 4.9 Hz, 2H), 2.58 (s, 3H), 1.83-1.62 (m, 8H), 1.45 (d, J = 6.1Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H).

Example 762N-(2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl)-4-methylbenzenesulfonamide

To a solution of Intermediate 662D (15 mg, 0.039 mmol) in DMF (1 mL) wasadded DIEA (0.069 mL, 0.393 mmol) and 4-methylbenzene-1-sulfonylchloride (9.00 mg, 0.047 mmol). The mixture was stirred at roomtemperature for 1 hour. The reaction was quenched by 0.2 ml of MeOH. Thereaction mixture was concentrated, redissolved in DMF, filtered, andpurified by preparative HPLC (Method D, 65 to 100% B in 22 minutes) toyield Example 762 (7.52 mg, 0.014 mmol, 35.7% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 8.70 (s, 1H), 8.52 (s, 1H), 7.89 (t, J=5.4 Hz, 1H), 7.80 (s,1H), 7.71 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.72 (s, 1H), 4.31(t, J=5.5 Hz, 2H), 4.08 (s, 3H), 3.21 (d, J=5.5 Hz, 2H), 2.71 (s, 3H),2.63 (s, 3H), 2.35 (s, 3H). LC-MS: method H, RT=1.23 min,): MS (ESI)m/z: 536.1 (M+H)⁺. Analytical HPLC Method B: 100% purity.

Example 7636-fluoro-5-methoxy-2-(2-(methoxymethyl)-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridine

Intermediate 763A: 5-bromo-3-fluoro-2-methoxy-4-methylpyridine

3-fluoro-2-methoxy-4-methylpyridine (0.500 g, 3.54 mmol) was dissolvedin AcOH (17.71 ml). Next, bromine (0.219 ml, 4.25 mmol) and sodiumacetate (0.581 g, 7.09 mmol) were added, and the reaction mixture washeated to 80° C. overnight. The reaction was carefully quenched withsaturated NaHCO₃ and extracted with EtOAc. The organic layer was washedwith 1 N NaOH, water, then brine, then dried (Na₂SO₄), filtered, andconcentrated in vacuo to yield Intermediate 763A (0.450 g, 2.045 mmol,57.7% yield) as a white solid. LC-MS: Method H, RT=1.02 min, MS (ESI)m/z: 220.1 (M+H)⁺.

Intermediate 763B: N-benzyl-5-fluoro-6-methoxy-4-methylpyridin-3-amine

Intermediate 763A (0.450 g, 2.045 mmol), copper(I) iodide (0.078 g,0.409 mmol), potassium carbonate (0.424 g, 3.07 mmol), and L-proline(0.094 g, 0.818 mmol) was added. The reaction mixture was placed undervacuum and backfilled with argon. The solids were dissolved in DMSO(20.45 ml) and stirred for 5 min. To the reaction was added benzylamine(0.268 ml, 2.454 mmol) and the reaction mixture was heated to 80° C.overnight. The reaction mixture was diluted with water and EtOAc. Thelayers were separated and the organic layer was washed with water,washed with brine, dried with sodium sulfate, and concentrated underreduced pressure. Purified on ISCO using a 40 g column with 0-100% EtOAcin hexanes gradient to yield Intermediate 763B (0.123 g, 0.499 mmol,24.42% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.27 (m, 6H), 4.33 (d,J=5.1 Hz, 2H), 3.93 (s, 3H), 3.48 (br. s., 1H), 2.12 (d, J=2.2 Hz, 3H).LC-MS: method H, RT=0.99 min, MS (ESI) m/z: 247.2 (M+H)⁺.

Intermediate 763C: 5-fluoro-6-methoxy-4-methylpyridin-3-amine

Intermediate 763B (0.150 g, 0.609 mmol) was dissolved in MeOH (6.09 ml)and palladium on carbon (0.130 g, 0.122 mmol) was added. The reactionmixture was placed under vacuum and back filled with argon three times.The reaction mixture was placed under vacuum and back filled withhydrogen (1.228 mg, 0.609 mmol) three times. The reaction mixture wasallowed to stir at room temperature for 3h. The reaction mixture wasfiltered and concentrated to yield Intermediate 763C (0.074 g, 0.474mmol, 78% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.41 (s,1H), 3.94 (s, 3H), 3.33 (br. s., 1H), 2.13 (d, J=2.0 Hz, 3H). LC-MS:method H, RT=0.55 min, MS (ESI) m/z: MS (ESI) m/z: 157.0 (M+H)⁺.

Intermediate 763D:6-fluoro-5-methoxy-7-methylthiazolo[5,4-b]pyridin-2-amine

Potassium thiocyanate (0.046 g, 0.474 mmol) was dissolved in acetic acid(1.137 ml) and cooled to 0° C. Intermediate 763C (0.074 g, 0.474 mmol)was dissolved in acetic acid (0.379 ml) and added dropwise. Bromine(0.049 ml, 0.948 mmol) was dissolved in acetic acid (0.379 ml) and addeddropwise to the reaction mixture. The reaction mixture was allowed towarm to room temperature and stir overnight. The reaction mixture wasconcentrated under reduced pressure. The resultant residue was dilutedwith water and neutralized with 1 N NaOH. The aqueous solution wasextracted with EtOAc×3. The combined organic layer was washed withbrine, dried with sodium sulfate, and concentrated under reducedpressure to yield Intermediate 763D (0.099 g, 0.464 mmol, 98% yield).LC-MS: Method H, RT=0.71 min, MS (ESI) m/z: MS (ESI) m/z: 214.1 (M+H)⁺.

Intermediate 763E:2-bromo-6-fluoro-5-methoxy-7-methylthiazolo[5,4-b]pyridine

Copper(II)bromide (0.178 g, 0.797 mmol) and t-butyl nitrite (0.095 ml,0.797 mmol) were dissolved in MeCN (1.876 ml) and allowed to stir 10minutes. Intermediate 763D (0.100 g, 0.469 mmol) was dissolved in MeCN(2.81 ml) and the copper solution was added. The reaction mixture wasstirred for 2.5h at 60° C. The reaction mixture was diluted with EtOAc,washed with 1 N HCl, saturated NaHCO₃, then brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purified on ISCO using a 12 gcolumn with 0-100% gradient of EtOAc in hexanes to yield Intermediate763E (0.098 g, 0.354 mmol, 75% yield). ¹H NMR (400 MHz, CDCl₃) δ 4.06(s, 1H), 2.60 (d, J=2.2 Hz, 1H). LC-MS: method H, RT=1.13 min, MS (ESI)m/z: MS (ESI) m/z: 277.1 (M+H)⁺.

Example 763

Intermediate I-2 (0.017 g, 0.054 mmol) and Intermediate 763E (0.015 g,0.054 mmol) were dissolved in DMF (1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(2.65 mg, 3.25 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Next, Na₂CO₃, 3 M aqueous solution(0.100 ml, 0.300 mmol) was added and the reaction mixture was degassedfor 5 minutes, then sealed and heated to 90° C. in a microwave for 30minutes. The reaction mixture was concentrated, redissolved in DMF,filtered, and purified by preparative HPLC (Method D, 60 to 100% B in 20minutes) to yield Example 763 (0.0008 g, 1.831 μmol, 3.38% yield):LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 385.2 (M+H)⁺. AnalyticalHPLC Method B: 88% purity.

Example 764(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate

Example 712 (50 mg, 0.084 mmol) was solvated in THF (1 mL) and cooled to−78° C. To this mixture was added diisobutylaluminum hydride (1 M intoluene) (0.253 mL, 0.253 mmol) and the reaction mixture was stirred for30 min. The reaction was quenched with 1 mL of a 1 M HCl solution at−78° C. The reaction mixture was allowed to thaw to room temperature andstirred for a total of 30 min. The mixture was diluted with EtOAc andwashed with saturated NH₄Cl before being dried over MgSO₄ and filteredover a pad of SiO₂ gel. The filtrate was concentrated and resubjected toidentical reaction conditions. The reaction mixture was diluted withsat′d Rochelle's salt and allowed to stir overnight. The reactionmixture was diluted with EtOAc and the layers were separated. Theaqueous layer was back extracted with EtOAc×3 and the combined organiclayer was washed with brine, dried with sodium sulfate, and concentratedunder reduced pressure to yield Example 764 (24.2 mg, 0.042 mmol, 49.8%yield): ¹H NMR (400 MHz, CDCl₃) δ 8.91-8.84 (m, 2H), 8.58 (d, J=1.8 Hz,1H), 8.55 (s, 1H), 8.01 (d, J=10.3 Hz, 1H), 7.85-7.74 (m, 1H), 6.69-6.53(m, 1H), 5.75 (dd, 2.5 Hz, 1H), 5.27 (dd, 2.6 Hz, 1H), 4.82 (d, J=4.8Hz, 2H), 4.16 (s, 3H), 3.49 (s, 1H), 2.67 (s, 3H), 1.50 (t, J=6.9 Hz,6H). LC-MS: method H, RT=1.23 min,): MS (ESI) m/z: 566.2 (M+H)⁺.Analytical HPLC Method B: 95% purity.

Example 765(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(6-(2-hydroxypropan-2-yl)pyridin-3-yl)carbamate

A solution of Example 715 (0.045 g, 0.076 mmol) in THF (1 mL) was cooledto −78° C. Methylmagnesium bromide (0.101 mL, 0.304 mmol) was added andthe mixture was allowed to warm to room temperature. The mixture wasstirred for 1 h. The reaction mixture was diluted with water and EtOAc.The layers were separated and the organic layer was washed with brine,dried with sodium sulfate, and concentrated under reduced pressure.Purified by ISCO using a 24 g column eluting with 0-70% EtOAc in DCM toyield Example 765 (0.015 g, 0.025 mmol, 33.3% yield). ¹H NMR (400 MHz,CDCl₃) δ 8.56 (d, J=1.8 Hz, 2H), 8.37 (s, 1H), 7.98 (d, J=10.3 Hz, 1H),7.77 (s, 1H), 7.31 (s, 2H), 6.59 (br. s., 1H), 5.66 (br. s., 1H), 5.23(dd, J=6.5, 3.0 Hz, 1H), 4.13 (s, 3H), 2.65 (s, 3H), 1.48 (d, J=6.6 Hz,3H), 1.46 (d, J=6.6 Hz, 3H), 1.25 (s, 6H). LC-MS: method H, RT=1.08 min,MS (ESI) m/z: 593.2 (M+H)⁺.

The methyl ketone(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(6-acetylpyridin-3-yl)carbamate was also isolated from the reaction asIntermediate 765A (0.020 g, 0.035 mmol 35% yield), which will be usedbelow. LC-MS: method H, RT=1.31 min, MS (ESI) m/z: 577.2 (M+H)⁺.Analytical HPLC Method B: 99% purity.

Example 766(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(6-(1-hydroxyethyl)pyridin-3-yl)carbamate

Intermediate 765A (0.020 g, 0.035 mmol) was dissolved in THF (0.347 ml)and cooled to −78° C. To the cooled reaction mixture was added DIBAL-Hin toluene (0.087 ml, 0.087 mmol), and the reaction mixture was allowedto stir for 1 h. The reaction mixture was allowed to warm to roomtemperature and saturated solution of Rochelle's salt was added. Theresulting mixture was allowed to stir overnight. The reaction mixturewas diluted with EtOAc and water. The layers were separated and theorganic layer was washed with brine, dried with sodium sulfate andconcentrated under reduced pressure. The reaction mixture wasconcentrated, redissolved in DMF, filtered, and purified by preparativeHPLC (Method D, 60 to 100% B in 15 minutes, then a 6 minute hold time)to yield the racemic product. The reaction was further purified 35%EtOH/65% CO₂ in a 15 min run, Lux 5 u Cellulose-4, 21×250 mm, 5 microncolumn, flow rate 45 mL/min, 150 Bar, 40° C. and UV detection was set to220 nm to yield Example 766 (3.3 mg, 5.48 μmol, 15.78% yield) as thefirst eluting isomer: ¹H NMR (500 MHz, DMSO-d₆) δ 9.79 (br. s., 1H),8.63 (br. s., 1H), 8.48 (s, 2H), 8.37 (d, J=10.7 Hz, 1H), 7.80 (s, 2H),5.64 (d, J=4.9 Hz, 1H), 5.15 (d, J=5.8 Hz, 1H), 4.07 (s, 3H), 3.56-3.48(m, 3H), 2.61 (s, 3H), 1.44 (d, J=6.4 Hz, 3H), 1.38 (d, J=6.4 Hz, 3H).LC-MS: method H, RT=1.08 min, MS (ESI) m/z: 579.2 (M+H)⁺. AnalyticalHPLC Method B: 99% purity.

Example 767(2R,3S)-3-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(6-(1-hydroxyethyl)pyridin-3-yl)carbamate

Intermediate 765A (0.020 g, 0.035 mmol) was dissolved in THF (0.347 ml)and cooled to −78° C. To the cooled reaction, was added DIBAL-H intoluene (0.087 ml, 0.087 mmol), and the reaction mixture was allowed tostir for 1 h. The reaction mixture was allowed to warm to roomtemperature and sat′d solution of Rochelle's salt was added. Thereaction mixture was allowed to stir overnight. The reaction mixture wasdiluted with EtOAc and water. The layers were separated and the organiclayer was washed with brine, dried with sodium sulfate and concentratedunder reduced pressure. The reaction mixture was concentrated,redissolved in DMF, filtered, and purified by preparative HPLC (MethodD, 60 to 100% B in 15 minutes, then a 6 minute hold time) to yield theracemic product. The reaction was further purified as above 35% EtOH/65%CO₂ in a 15 min run, Lux 5 u Cellulose-4, 21×250 mm, 5 micron column,flow rate 45 mL/min, 150 Bar, 40° C. and UV detection was set to 220 nmto yield Example 767 (2.9 mg, 4.66 μmol, 13.4% yield) as the secondeluting isomer: ¹H NMR (500 MHz, DMSO-d₆) δ 9.80-9.64 (m, 1H), 8.63 (s,1H), 8.48 (s, 2H), 8.37 (d, J=10.7 Hz, 1H), 7.80 (s, 2H), 7.43-7.35 (m,1H), 5.69-5.60 (m, 1H), 5.22-5.10 (m, 1H), 4.64 (d, J=6.4 Hz, 1H), 4.07(s, 3H), 3.55 (br. s., 4H), 2.61 (s, 3H), 1.45 (d, J=6.7 Hz, 3H), 1.38(d, J=6.7 Hz, 3H). LC-MS: method H, RT=1.08 min, MS (ESI) m/z: 579.2(M+H)⁺. Analytical HPLC Method B: 99% purity.

Example 768(R)-1-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate

Example 689 (50 mg, 0.086 mmol) was solvated in THF (1 mL) and cooled to−78° C. To this mixture was added diisobutylaluminum hydride (1 M intoluene) (0.259 mL, 0.259 mmol) and stirred for 30 min. The reaction wasquenched with 1 mL of a 1 M HCl solution at −78° C. The reaction mixturewas allowed to thaw to room temperature and stirred for a total of 30min. The mixture was diluted with EtOAc and washed with saturated NH₄Clbefore being dried over MgSO₄ and filtered over a pad of SiO₂ gel toremove aluminates. The filtrate was concentrated and resubjected toidentical reaction conditions. The reaction mixture was diluted withsat'd Rochelle's salt and allowed to stir overnight. The reactionmixture was diluted with EtOAc and the layers were separated. Theaqueous layer was back extracted with EtOAc×3 and the combined organiclayer was washed with brine, dried with sodium sulfate, and concentratedunder reduced pressure. The reaction was purified on ISCO using a 12 gcolumn eluting with 0-100% EtOAc in hexanes to yield Example 768 (19.60mg, 0.034 mmol, 39.1% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 8.88 (br. s., 2H), 8.59 (s, 1H), 8.57 (s, 1H), 8.03 (d, J=10.3 Hz,1H), 7.81 (s, 1H), 6.67 (br. s., 1H), 5.44 (dt, J=6.3, 3.0 Hz, 1H),4.89-4.78 (m, 3H), 4.57 (d, J=6.2 Hz, 1H), 4.16 (s, 3H), 3.50 (br. s.,1H), 2.68 (s, 3H), 1.53 (d, J=6.4 Hz, 3H). MS (ESI) m/z: 552.1 (M+H)⁺.LC-MS: method H, RT=1.12 min, MS (ESI) m/z: 552.1 (M+H)⁺. AnalyticalHPLC Method B: 95% purity.

Example 769(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate I-121 (15 mg, 0.047 mmol), Intermediate I-135 (21.26 mg,0.052 mmol) and PdCl₂(dppf) (2.061 mg, 2.82 μmol) were dissolved indioxane (469 μl) and Na₂CO₃ (211 μl, 0.422 mmol) and heated to 100° C.in an oil bath for 2 hours. The reaction mixture was cooled to ambienttemperature, diluted with EtOAc, washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The reaction mixture wasconcentrated, redissolved in DMF, filtered, and purified by preparativeHPLC (Method D, 25 to 100% B in 15 minutes) to yield Example 769 (7.2,12.65 mmol, 2.70E+04% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 9.81 (br. s.,1H), 8.77 (br. s., 1H), 8.68 (br. s., 2H), 8.55 (s, 1H), 8.41 (d, J=10.7Hz, 1H), 8.19 (s, 1H), 7.93 (br. s., 1H), 5.73 (d, J=6.4 Hz, 1H), 5.13(d, J=6.1 Hz, 1H), 4.00 (s, 3H), 2.46 (s, 3H), 1.44 (d, J=6.4 Hz, 3H),1.38 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.42, MS (ESI) m/z: 569.1(M+H)⁺. Analytical HPLC Method B: 100%

Examples 770 to 775

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 769 and theexamples above. If necessary, removal of silyl protecting groups wasaccomplished by treatment of the protected compound with a solution of90% MeOH, 9.9% water, and 0.1% TFA or MeOH/HCl (20/1) solution to affordthe desired compound.

LCMS LCMS Ex. Boronic [M + H]⁺ RT (Min) No. Structure acid Chloride m/zMethod H NMR 770

I-121 I-139 555.1 1.40 ¹H NMR (500 MHz, DMSO-d₆) δ 10.03-9.92 (m, 1H),8.82 (br. s., 1H), 8.73 (br. s., 2H), 8.56 (s, 1H), 8.44 (d, J = 10.7Hz, 1H), 8.19 (s, 1H), 7.93 (br. s., 1H), 5.28 (br. s., 1H), 4.84 (d, J= 11.6 Hz, 1H), 4.55 (dd, J = 11.7, 6.3 Hz, 1H), 4.00 (s, 3H), 2.50-2.50(m, 3H), 1.43 (d, J = 6.4 Hz, 3H). 771

I-124 I-139 535.2 1.03 ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (br. s., 2H),8.58 (br. s., 1H), 8.47-8.38 (m, 1H), 7.89 (d, J = 9.8 Hz, 1H), 7.21-6.97 (m, 2H), 5.28 (br. s., 1H), 4.84 (d, J = 11.6 Hz, 1H), 4.62-4.50(m, 1H), 4.00 (s, 3H), 2.61 (s, 3H), 1 48-1.40 (m, 3H). 772

I-136 I-130 552.2 1.09 ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (br. s., 1H),8.66 (br. s., 2H), 8.41 (d, J = 9.5 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H),7.93-7.82 (m, 3H), 5.04 (d, J = 6.4 Hz, 1H), 4.75 (d, J = 6.1 Hz, 1H),3.93 (s, 3H), 2.48 (br. s., 3H), 1.33 (br. s., 6H). 773

I-140 I-130 564.3 0.92 ¹H NMR (500 MHz, DMSO-d₆) δ 9.96 (br. s, 1H),8.83 (br. s., 1H), 8.75 (br. s., 2H), 8.06- 7.99 (m, 2H), 7.98-7.93 (m,2H), 5.22-5.05 (m, 1H), 4.81 (br. s., 2H), 4.00 (br. s., 3H), 2.55 (br.s., 5H), 1.40 (br. s., 6H). 774

I-121 I-137 615.1 1.18 ¹H NMR (500 MHz, DMSO-d₆) δ 9.66 (br. s., 1H),8.76 (br. s., 1H), 8.59-8.56 (m, 2H), 8.54 (d, J = 2.1 Hz, 1H), 8.40 (d,J = 10.7 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 2.7 Hz, 1H),5.72 (dd, J = 6.6, 2.3 Hz, 1H), 5.11 (dd, J = 6.4, 2.1 Hz, 1H), 4.87 (s,1H), 4.22-4.10 (m, 2H), 3.99 (s, 3H), 3.66 (d, J = 5.5 Hz, 2H), 1.43 (d,J = 6.4 Hz, 3H), 1.37 (d, J = 6.7 Hz, 3H). 775

I-124 I-137 595.0 1.08 ¹H NMR (500 MHz, DMSO-d₆) δ 9.71-9.54 (m, 1H),8.65 (d, J = 2.1 Hz, 1H), 8.56-8.46 (m, 3H), 8.33 (d, J = 10.7 Hz, 1H),7.83-7.72 (m, 2H), 5.63 (dd, J = 6.6, 2.3 Hz, 1H), 5.14-4.99 (m, 1H),4.76 (s, 1H), 4.19-4.03 (m, 2H), 3.92 (s, 3H), 3.60 (d, J = 5.5 Hz, 2H),2.53 (s, 3H), 1.36 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 6.7 Hz, 3H).

Example 776(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(5-fluoropyridin-3-yl)carbamate

Intermediate 776A:(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol

Intermediate I-121 (75 mg, 0.235 mmol), Intermediate I-133 (64.7 mg,0.235 mmol) and PdCl₂(dppf) (10.30 mg, 0.014 mmol) were dissolved indioxane (2347 μl) and Na₂CO₃ (1056 μl, 2.112 mmol) and heated to 100° C.in an oil bath for 2 hours. The reaction mixture was cooled to ambienttemperature, diluted with EtOAc, washed with water, then brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. Purified on ISCO using0-100% EtOAc in DCM on a 24 g column to yield Intermediate 776A (0.054g, 0.124 mmol, 53.0% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ8.80 (dd, J=16.2, 2.5 Hz, 2H), 8.02 (d, J=10.3 Hz, 1H), 7.85 (d, J=2.4Hz, 1H), 7.41 (d, J=2.9 Hz, 1H), 5.48-5.35 (m, 1H), 4.22-4.10 (m, 1H),4.03 (s, 3H), 2.56-2.47 (m, 1H), 1.46 (d, J=6.4 Hz, 3H), 1.33 (d, J=6.6Hz, 3H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 433.9 (M+H)⁺.

Intermediate 776B:(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ylcarbonochloridate

To a solution of Intermediate 776A (0.054 g, 0.124 mmol) in THF (5 mL)at room temperature was added 15% phosgene in toluene (0.439 mL, 0.622mmol), and the mixture was stirred at room temperature overnight.Solvent was completely removed to give Intermediate 776B (0.062 g, 0.112mmol, 90% yield) as a yellow solid. LC-MS: method H, RT=1.39 min MS(ESI) m/z: 495.9 (M+H)⁺.

Example 776

5-fluoropyridin-3-amine (3.39 mg, 0.030 mmol) and pyridine (0.016 mL,0.201 mmol) were dissolved in DCM (2 mL). To this solution was addedIntermediate 776B (0.010 g, 0.020 mmol) as a solution in DCM (1 mL). Thereaction mixture was allowed to stir for 1 h. The reaction mixture wasconcentrated under reduced pressure, redissolved in DMF, filtered, andpurified by preparative HPLC (Method D, 25 to 100% B in 15 minutes) toyield Example 776 (0.0072 g, 0.013 mmol, 62.5% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 10.07 (br. s., 1H), 8.76 (s, 1H), 8.54 (s, 1H), 8.44-8.37 (m,2H), 8.18 (s, 1H), 8.14 (s, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.81 (br. s.,1H), 5.71 (d, J=6.1 Hz, 1H), 5.17 (d, J=5.2 Hz, 1H), 4.00 (s, 3H), 1.46(d, J=6.4 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.28 min,MS (ESI) m/z: 572.0 (M+H)⁺. Analytical HPLC Method B: 100% purity.

Examples 777 to 791

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 776 and theexamples above. If necessary, removal of silyl protecting groups wasaccomplished by treatment of the protected compound with a solution of90% MeOH, 9.9% water, and 0.1% TFA or MeOH/HCl (20/1) solution to affordthe desired compound.

LCMS LCMS Ex. [M + H]⁺ RT (Min) No. Structure Amine m/z Method H NMR 777

610.0 1.50 ¹H NMR (500 MHz, DMSO- d₆) δ 11.39 (s, 1H), 9.53 (br. s.,1H), 8.70 (br. s., 1H), 8.52 (s, 1H), 8.37 (d, J = 11.0 Hz, 1H), 8.14(s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.37 (br. s, 1H), 7.09 (br. s., 1H),6.90 (d, J = 8.2 Hz, 1H), 5.66 (d, J = 4.6 Hz, 1H), 5.13 (d, J = 4.3 Hz,1H), 3.98 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H).778

656.0 1.08 ¹H NMR (500 MHz, DMSO- d₆) δ 9.90 (s, 1H), 8.69 (d, J = 2.4Hz, 1H), 8.50 (s, 1H), 8.35 (d, J = 10.7 Hz, 1H), 8.13 (s, 1H),7.94-7.84 (m, 2H), 7.00-6.95 (m, 1H), 6.76 (br. s, 1H), 5.77-5.64 (m,1H), 5.23-5.09 (m, 1H), 4.19 (dt, J = 19.8, 7.4 Hz, 2H), 3.97 (s, 3H),3.49 (s, 1H), 1.74-1.68 (m, 2H), 1.44 (d, J = 6.4 Hz, 3H), 1.38 (d, J =6.4 Hz, 3H), 1.10 (s, 6H). 779

614.1 1.06 ¹H NMR (500 MHz, DMSO- d₆) δ 9.49 (br. s., 1H), 8.79 (br. s.,1H), 8.56 (s, 1H), 8.42 (d, J = 10.7 Hz, 1H), 8.19 (s, 1H), 8.12 (br.s., 1H), 7.93 (br. s., 1H), 7.76 (br. s., 1H), 6.72 (br. s., 1H), 5.68(d, J = 6.7 Hz, 1H), 5.12 (d, J = 6.7 Hz, 1H), 4.18-4.06 (m, 2H), 4.00(s, 3H), 3.65 (t, J = 4.9 Hz, 2H), 3.36 (br. s., 1H), 1.45 (d, J = 6.4Hz, 3H), 1.38 (d, J = 6.7 Hz, 3H). 780

614.1 1.06 ¹H NMR (500 MHz, DMSO- d₆) δ 9.95 (s, 1H), 8.74 (d, J = 2.7Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.41 (d, J = 11.0 Hz, 1H), 8.18 (d, J= 1.8 Hz, 1H), 7.94-7.88 (m, 2H), 7.02 (d, J = 5.5 Hz, 1H), 6.82 (s,1H), 5.70 (d, J = 6.7 Hz, 1H), 5.16 (d, J = 6.7 Hz, 1H), 4.14 (dq, J =19.5, 5.5 Hz, 2H), 4.00 (s, 3H), 3.61 (d, J = 4.0 Hz, 2H), 3.39 (s, 1H),1.45 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H). 781

598.1 1.06 ¹H NMR (500 MHz, DMSO- d6) δ 9.74 (br. s., 1H), 8.80 (d, J =2.4 Hz, 1H), 8.56 (s, 1H), 8.49 (br. s., 1H), 8.42 (d, J = 11.0 Hz, 1H),8.19 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.79 (br. s., 1H), 7.26-7.18 (m,1H), 5.66 (d, J = 6.4 Hz, 1H), 5.16 (d, J = 7.3 Hz, 1H), 4.00 (s, 3H),3.66 (t, J = 6.9 Hz, 2H), 3.38 (br. s., 1H), 2.77 (q, J = 6.1 Hz, 2H),1.46 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 3H). 782

570.9 1.25 ¹H NMR (500 MHz, DMSO- d₆) δ 10.21-10.16 (m, 1H), 8.87 (d, J= 2.7 Hz, 1H), 8.63 (s, 1H), 8.47 (br. s., 1H), 8.20 (br. s., 2H), 8.06(d, J = 8.2 Hz, 1H), 7.98 (d, J = 11.3 Hz, 1H), 7.95 (d, J = 2.4 Hz,1H), 7.83 (d, J = 12.2 Hz, 1H), 5.13 (br. s., 1H), 4.82 (br. s., 1H),4.00 (s, 3H), 1.49-1.34 (m, 6H). 783

622.9 1.31 ¹H NMR (500 MHz, DMSO- d₆) δ 10.32 (s, 1H), 8.83 (d, J = 2.7Hz, 1H), 8.77 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 1.8 Hz,1H), 8.14-8.10 (m, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 11.6 Hz,1H), 7.92 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 5.15 (dd, J =6.6, 2.3 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 3.99 (s, 3H), 1.42 (dd, J =6.0, 3.8 Hz, 6H). 784

582.9 1.26 ¹H NMR (500 MHz, DMSO- d₆) δ 9.65-9.57 (m, 1H), 8.85 (d, J =2.1 Hz, 1H), 8.61 (s, 1H), 8.23-8.20 (m, 1H), 8.18 (s, 1H), 8.03 (d, J =7.9 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.93 (br. s., 1H), 7.82-7.73 (m,1H), 6.76 (d, J = 8.2 Hz, 1H), 5.09 (d, J = 4.6 Hz, 1H), 4.80 (d, J =5.5 Hz, 1H), 3.99 (s, 3H), 3.78 (s, 3H), 1.39 (dd, J = 9.9, 6.6 Hz, 6H).785

583.0 1.05 ¹H NMR (500 MHz, DMSO- d₆) d 9.91 (br. s., 1H), 8.85 (d, J =2.4 Hz, 1H), 8.61 (s, 1H), 8.24 (br. s., 1H), 8.18 (s, 1H), 8.04 (d, J =8.2 Hz, 1H), 7.99-7.91 (m, 3H), 7.55 (br. s., 1H), 5.12 (d, J = 4.6 Hz,1H), 4.81 (d, J = 4.0 Hz, 1H), 3.99 (s, 3H), 3.78 (s, 3H), 1.41 (t, J =6.6 Hz, 6H). 786

577.9 1.25 ¹H NMR (500 MHz, DMSO- d₆) d 10.28 (br. s., 1H), 8.87-8.81(m, 2H), 8.60 (s, 2H), 8.25 (br. s., 1H), 8.18 (s, 1H), 8.04 (d, J = 8.2Hz, 1H), 7.96 (d, J = 11.3 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 5.14 (d, J= 4.3 Hz, 1H), 4.85 (d, J = 4.0 Hz, 1H), 3.99 (s, 3H), 1.42 (d, J = 4.9Hz, 6H). 787

582.8 1.02 ¹H NMR (500 MHz, DMSO- d₆) d 9.71 (br. s., 1H), 8.86 (d, J =2.4 Hz, 1H), 8.62 (s, 1H), 8.33 (br. s., 1H), 8.18 (s, 1H), 8.04 (d, J =8.2 Hz, 1H), 7.96 (d, J = 11.6 Hz, 1H), 7.93 (br. s., 1H), 7.63 (br. s.,1H), 5.10 (d, J = 4.0 Hz, 1H), 4.81 (d, J = 4.3 Hz, 1H), 4.00 (s, 3H),2.33 (s, 3H), 2.18 (s, 3H), 1.40 (t, J = 7.3 Hz, 6H). 788

552.9 1.02 ¹H NMR (500 MHz, DMSO- d₆) δ 9.91 (br. s., 1H), 8.86 (d, J =2.7 Hz, 1H), 8.65 (br. s., 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.21 (d, J =4.3 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.6Hz, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.92-7.88 (m, 1H), 7.33 (dd, J = 8.2,4.6 Hz, 1H), 5.22-5.08 (m, 1H), 4.81 (d, J = 3.7 Hz, 1H), 4.00 (s, 3H),1.41 (t, J = 6.7 Hz, 6H). 789

571.0 1.27 ¹H NMR (500 MHz, DMSO- d₆) d 10.01-9.90 (m, 1H), 8.85 (d, J =2.4 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.27 (br. s., 1H), 8.18 (d, J =1.8 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 11.6 Hz, 1H), 7.93(d, J = 2.4 Hz, 1H), 7.12 (d, J = 6.4 Hz, 1H), 5.12 (dd, J = 6.6, 2.6Hz, 1H), 4.81 (d, J = 3.7 Hz, 1H), 4.00 (s, 3H), 1.41 (t, J = 6.4 Hz,6H). 790

552.9 1.02 ¹H NMR (500 MHz, DMSO- d₆) δ 10.31 (s, 1H), 8.86 (d, J = 2.7Hz, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.41 (d, J = 5.5 Hz, 2H), 8.19 (d, J= 1.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 11.3 Hz, 1H), 7.94(d, J = 2.4 Hz, 1H), 7.52 (d, J = 5.8 Hz, 2H), 5.16 (d, J = 4.0 Hz, 1H),4.82 (d, J = 3.7 Hz, 1H), 4.00 (s, 3H), 1.48-1.36 (m, 6H). 791

549.2 1.06 ¹H NMR (500 MHz, DMSO- d₆) δ 9.76 (br. s., 1H), 8.65 (br. s.,2H), 8.49 (s, 1H), 8.34 (d, J = 10.7 Hz, 1H), 7.80 (d, J = 9.8 Hz, 2H),7.61-7.33 (m, 1H), 7.18-6.88 (m, 1H), 5.65 (d, J = 6.4 Hz, 1H), 5.06 (d,J = 6.4 Hz, 1H), 3.92 (s, 3H), 2.54 (s, 3H), 2.41 (s, 3H), 1.37 (d, J =6.1 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H).

Example 792(2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate

Intermediate 792A: methyl5-(((((2R,3S)-3-((6-fluoro-2-(3-methoxy-6-methylquinolin-8-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate

Intermediate I-124 (6.56 mg, 0.022 mmol), Intermediate I-141 (10 mg,0.022 mmol), and PdCl₂(dppf) (0.963 mg, 1.316 μmol) were dissolved indioxane (219 μl) and 3 M aqueous Na₂CO₃ (99 μl, 0.197 mmol) was added.The reaction mixture was heated to 100° C. in an oil bath for 2 hours.The reaction mixture was cooled to ambient temperature, diluted withEtOAc, washed with water, washed with brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. The reaction material was dissolved in DCMand filtered. Purified on ISCO using 0-100% EtOAc in DCM on a 4 g columnto yield Intermediate 792A (7.5 mg, 0.013 mmol, 57.7% yield) as a yellowsolid. LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 593.1 (M+H)⁺.

Example 792

Intermediate 792A (7.5 mg, 0.013 mmol) was dissolved in THF (127 μl) andlithium borohydride (0.276 mg, 0.013 mmol) was added in one portion. Thereaction mixture was allowed to stir at room temperature for 3 h.Residue was dissolved in THF and air was bubbled through the reactionuntil the solvent was evaporated. The reaction material was dissolved inDMF, filtered, and purified by preparative HPLC (Method D, 45 to 90% Bin 15 minutes) to yield Example 792 (1.7 mg, 2.95 μmol, 23.32% yield):¹H NMR (500 MHz, DMSO-d₆) δ 9.96 (br. s., 1H), 8.80 (br. s., 2H), 8.74(br. s., 1H), 8.57 (br. s., 1H), 8.41 (d, J=10.7 Hz, 1H), 7.88 (d,J=10.4 Hz, 2H), 5.70 (br. s., 1H), 5.17 (br. s., 1H), 4.49 (br. s., 2H),4.00 (br. s., 3H), 3.84-3.34 (m, 1H), 2.61 (br. s., 3H), 1.54-1.34 (m,6H). LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 565.2 (M+H)⁺.Analytical HPLC Method B: 98% purity.

Example 793(2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate

Intermediate 793A: methyl5-(((((2R,3S)-3-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate

Intermediate I-121 (7.01 mg, 0.022 mmol), Intermediate I-141 (10 mg,0.022 mmol), and PdCl₂(dppf) (0.963 mg, 1.316 μmol) were dissolved indioxane (219 μl) and 3 M aqueous Na₂CO₃ (99 μl, 0.197 mmol) was added.The reaction mixture was heated to 100° C. in an oil bath for 2 hours.The reaction mixture was cooled to ambient temperature, diluted withEtOAc, washed with water, washed with brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. The reaction material was dissolved in DCMand filtered. Purified on ISCO using 0-100% EtOAc in DCM on a 4 g columnto yield Intermediate 793A (5.9 mg, 0.0096 mmol, 44% yield) as a yellowsolid. LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 613.1 (M+H)⁺.

Example 793

Intermediate 793A (5.9 mg, 0.009 mmol) was dissolved in THF (127 μl) andlithium borohydride (0.276 mg, 0.013 mmol) was added in one portion. Thereaction mixture was allowed to stir at room temperature for 3 h.Residue was dissolved in THF and air was bubbled through the reactionuntil the solvent was evaporated. The reaction material was dissolved inDMF, filtered, and purified by preparative HPLC (Method D, 45 to 90% Bin 15 minutes) to yield Example 793 (1.1 mg, 1.79 μmol, 19% yield): ¹HNMR (500 MHz, DMSO-d₆) δ 9.94 (br. s., 1H), 8.91-8.71 (m, 2H), 8.58 (br.s., 1H), 8.45 (d, J=10.1 Hz, 1H), 8.21 (br. s., 1H), 7.95 (br. s., 1H),7.70 (d, J=14.3 Hz, 1H), 5.71 (br. s., 1H), 5.17 (br. s., 1H), 4.48 (br.s., 2H), 4.00 (br. s., 3H), 3.43-3.28 (m, 1H), 1.52-1.36 (m, 6H). LC-MS:method H, RT=0.95 min, MS (ESI) m/z: 585.1 (M+H)⁺. Analytical HPLCMethod B: 95% purity.

Example 794(R)-1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate

Intermediate 794A: (R)-methyl5-((((1-((2-(6-chloro-3-methoxyquinolin-8-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate

Intermediate I-121 (7.23 mg, 0.022 mmol), Intermediate I-142 (10 mg,0.022 mmol) and PdCl₂(dppf) (0.963 mg, 1.316 μmol) were dissolved indioxane (219 μl) and 3M aqueous Na₂CO₃ (99 μl, 0.197 mmol) was added.The reaction mixture was heated to 100° C. in an oil bath for 2 hours.The reaction mixture was cooled to ambient temperature, diluted withEtOAc, washed with water, washed with brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. The material was dissolved in DCM andfiltered. Purified on ISCO using 0-100% EtOAc in DCM on a 4 g column toyield Intermediate 792A (4.5 mg, 0.0075 mmol, 33% yield) as a yellowsolid. LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 599.1 (M+H)⁺.

Example 794

Intermediate 794A (4.5 mg, 0.008 mmol) was dissolved in THF (127 μl) andlithium borohydride (0.276 mg, 0.013 mmol) was added in one portion. Thereaction mixture was allowed to stir at room temperature for 3 h.Residue was dissolved in THF and air was bubbled through the reactionmixture until the solvent was evaporated. The mixture was dissolved inDMF, filtered, and purified by preparative HPLC (Method D, 45 to 90% Bin 15 minutes) to yield Example 794 (0.8 mg, 1.33 μmol, 18% yield). ¹HNMR (500 MHz, DMSO-d₆) δ 10.08 (br. s., 1H), 8.84 (d, J=18.0 Hz, 3H),8.59 (br. s., 1H), 8.48 (d, J=9.8 Hz, 1H), 8.22 (br. s., 1H), 7.96 (br.s., 1H), 5.30 (br. s., 1H), 4.84 (d, J=11.9 Hz, 1H), 4.60-4.54 (m, 1H),4.51 (br. s., 2H), 4.01 (br. s., 3H), 3.41-3.23 (m, 1H), 1.43 (br. s.,3H). LC-MS: method H, RT=0.96 min, MS (ESI) m/z: 571.1 (M+H)⁺.Analytical HPLC Method B: 95% purity.

Example 795(2R,3S)-3-((4-chloro-2-(6-chloro-3-methoxyquinolin-8-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate

Intermediate I-97 (10.83 mg, 0.035 mmol) and pyridine (0.019 mL, 0.236mmol) were dissolved in DCM (2 mL). To this solution was addedIntermediate I-143 (0.0125 g, 0.024 mmol) as a solution in DCM (1 mL).The reaction mixture was allowed to stir for 30 min. The reactionmixture was concentrated under reduced pressure and dissolved in 2 mL of1:1 THF:MeOH solution and CSA (5.48 mg, 0.024 mmol) was added. Thereaction mixture was allowed to stir at room temperature for 2 h. TEA(0.033 mL, 0.236 mmol) was added to quench the CSA, and the reactionmixture was concentrated and dissolved in 2 mL of DMF, filtered, andpurified by preparative HPLC (Method D, 50 to 100% B in 20 minutes) toyield Example 795 (0.0075 g, 0.012 mmol, 49.0% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 9.80 (br. s., 1H), 8.82 (d, J=2.1 Hz, 1H), 8.59 (br. s., 3H),8.18 (s, 1H), 8.05 (d, J=7.3 Hz, 1H), 7.92 (br. s., 1H), 5.11 (d, J=4.9Hz, 1H), 4.86 (br. s., 1H), 4.23 (br. s., 2H), 3.99 (s, 3H), 3.68 (d,J=4.9 Hz, 2H), 3.34 (br. s., 1H), 1.41 (dd, J=15.3, 6.1 Hz, 6H). LC-MS:method H, RT=1.23 min, MS (ESI) m/z: 647.9 (M+H)⁺. Analytical HPLCMethod B: 100% purity.

Examples 796 to 804

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 795 and theexamples above.

LCMS LCMS Ex. [M + H]⁺ RT (Min) No. Structure Amine m/z Method H NMR 796

663.9 1.26 ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (br. s., 1H), 8.80 (br. s.,1H), 8.63- 8.54 (m, 3H), 8.16 (s, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.90(br. s., 1H), 5.11 (d, J = 7.0 Hz, 1H), 4.85 (d, J = 7.0 Hz, 1H), 4.07(d, J = 6.4 Hz, 1H), 4.02 (br. s., 1H), 3.99 (s, 3H), 3.96- 3.89 (m,1H), 3.36 (d, J = 4.6 Hz, 1H), 1.41 (dd, J = 15.6, 6.1 Hz, 6H), 1.11 (d,J = 6.1 Hz, 3H). 797

605.1 1.33 ¹H NMR (500 MHz, DMSO-d₆) δ 9.94 (br. s., 1H), 8.78 (d, J =2.7 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.30-8.24 (m, 1H), 8.14 (d, J =2.1 Hz, 1H), 8.02 (d, J = 7.3 Hz, 2H), 7.88 (d, J = 2.7 Hz, 1H), 7.11(d, J = 7.0 Hz, 1H), 5.13 (dd, J = 6.4, 2.4 Hz, 1H), 4.84 (d, J = 4.0Hz, 1H), 3.98 (s, 3H), 1.42 (dd, J = 16.2, 6.4 Hz, 6H). 798

588.8 1.10 ¹H NMR (500 MHz, DMSO-d₆) δ 11.00 (s, 1H), 8.82 (d, J = 2.7Hz, 1H), 8.59 (d, J = 2.4 Hz, 3H), 8.18 (d, J = 2.1 Hz, 1H), 8.07 (d, J= 7.6 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.79 (d,J = 6.4 Hz, 2H), 5.22(dd, J = 6.7, 2.4 Hz, 1H), 4.95-4.77 (m, 1H), 3.99 (s, 3H), 1.44 (t, J =7.0 Hz, 6H). 799

588.8 1.11 ¹H NMR (500 MHz, DMSO-d₆) δ 9.91 (br. s., 1H), 8.83 (d, J =3.1 Hz, 1H), 8.65 (br. s., 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.23- 8.17 (m,2H), 8.07 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 2.7 Hz, 2H), 7.33 (dd, J =8.1, 4.7 Hz, 1H), 5.15 (dd, J = 6.4, 2.7 Hz, 1H), 4.92-4.77 (m, 1H),4.00 (s, 3H), 1.42 (dd, J = 15.3, 6.4 Hz, 6H). 800

616.8 1.12 ¹H NMR (500 MHz, DMSO-d₆) δ 10.15 (br. s., 1H), 8.83 (d, J =2.7 Hz, 1H), 8.61 (d, J = 2.1 Hz, 1H), 8.50 (br. s., 1H), 8.20 (d, J =2.1 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.97- 7.85 (m, 2H), 5.14 (d, J =6.4 Hz, 1H), 4.87 (d, J = 4.0 Hz, 1H), 4.00 (s, 3H), 2.42 (s, 3H), 2.26(s, 3H), 1.42 (dd, J = 14.2, 6.6 Hz, 6H). 801

618.8 1.33 ¹H NMR (500 MHz, DMSO-d₆) δ 9.60 (br. s., 1H), 8.82 (d, J =2.7 Hz, 1H), 8.60 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 2.1 Hz, 2H), 8.04(d, J = 7.3 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.76 (br. s., 1H), 6.75(d, J = 7.9 Hz, 1H), 5.10 (dd, J = 6.6, 2.6 Hz, 1H), 4.83 (dd, J = 6.4,2.7 Hz, 1H), 3.99 (s, 3H), 3.77 (s, 3H), 1.42 (d, J = 6.1 Hz, 3H), 1.39(d, J = 6.4 Hz, 3H). 802

613.8 1.32 ¹H NMR (500 MHz, DMSO-d₆) δ 10.27 (br. s., 1H), 8.81 (d, J =2.7 Hz, 2H), 8.62-8.56 (m, 2H), 8.25 (br. s., 1H), 8.17 (d, J = 1.8 Hz,1H), 8.05 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 5.15 (dd, J =6.6, 2.3 Hz, 1H), 4.88 (d, J = 4.0 Hz, 1H), 3.99 (s, 3H), 1.43 (dd, J =12.2, 6.4 Hz, 6H). 803

618.9 1.13 ¹H NMR (500 MHz, DMSO-d₆) δ 9.86 (br. s., 1H), 8.76 (d, J =2.7 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.19 (br. s., 1H), 8.12 (d, J =2.4 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J = 2.7Hz, 1H), 7.50 (br. s., 1H), 5.09 (dd, J = 6.6, 2.6 Hz, 1H), 4.89-4.68(m, 1H), 3.94 (s, 3H), 3.73 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.35 (d,J = 6.7 Hz, 3H). 804

605.1 1.32 ¹H NMR (500 MHz, DMSO-d₆) δ 10.18 (br. s., 1H), 8.79 (d, J =2.7 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.46 (br. s., 1H), 8.19 (d, J =2.4 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.89(d, J = 2.7 Hz, 1H), 7.82 (d, J = 10.4 Hz, 1H), 5.15 (dd, J = 6.6, 2.6Hz, 1H), 4.85 (d, J = 3.7 Hz, 1H), 3.98 (s, 3H), 1.42 (dd, J = 14.2, 6.6Hz, 6H).

Example 8061-(6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)benzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 806A: 4-bromo-6-fluorobenzo[d]thiazol-2-amine

2-Bromo-4-fluoroaniline (0.54 g, 2.84 mmol) was dissolved in MeCN (14.21ml). Ammonium thiocyanate (0.324 g, 4.26 mmol) was added to the reactionmixture followed by benzyltrimethylammonium tribromide (1.108 g, 2.84mmol), and the reaction mixture was allowed to stir for 12 hours. Thereaction mixture was diluted with saturated aqueous NaHCO₃, and thesolids were collected by suction filtration and washed with water toyield Intermediate 806A (0.700 g, 2.84 mmol, 100%). ¹H NMR (400 MHz,MeOH₄) δ 7.41 (dd, J=8.0, 2.5 Hz, 1H), 7.26 (dd, 2.5 Hz, 1H). LC-MS:method H, RT=0.81 min, MS (ESI) m/z: 247/249 (M+H)⁺.

Intermediate 806B:1-(2-amino-6-fluorobenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 806A (50 mg, 0.202 mmol) was dissolved in THF (2024 μl).NaH (8.90 mg, 0.223 mmol) was added and the reaction mixture was stirredfor 30 min. The reaction mixture was cooled to −78° C. and BuLi (106 μl,0.243 mmol) was added. The reaction mixture was allowed to stir for 30min. Pivalaldehyde (17.43 mg, 0.202 mmol) was added, and the reactionmixture was allowed to warm to ambient temperature. The reaction mixturewas stirred for 10 min then diluted with water and EtOAc. The layerswere separated and the aqueous layer was back extracted with EtOAc. Thecombined organic layer was washed with water, dried with sodium sulfate,and concentrated under reduced pressure to yield Intermediate 806B(0.064 g, 0.151 mmol, 75% yield). Used without further purification as a60% pure mixture. LC-MS: method H, RT=0.56 min, MS (ESI) m/z: 255.2(M+H)⁺.

Intermediate 806C:1-(2-chloro-6-fluorobenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Copper(II) chloride (0.058 g, 0.434 mmol) and t-butyl nitrite (0.052 ml,0.434 mmol) were dissolved in MeCN (1.022 ml) and allowed to stir 10minutes. Intermediate 806B (0.065 g, 0.256 mmol) was dissolved in MeCN(1.533 ml), and the copper solution was added. The reaction mixture wasstirred for 2.5 h at 60° C. The reaction mixture was diluted with EtOAcand water. The layers were separated, and the organic layer was washedwith 1 N HCl, washed with saturated aqueous NaHCO₃, washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude materialwas purified on ISCO using a 12 g column with 0-100% gradient of EtOAcin hexanes to yield Intermediate 806C (0.008 g, 0.029 mmol, 11.43%yield) as a white solid. LC-MS: method H, RT=1.14 min, MS (ESI) m/z:274.1 (M+H)⁺.

Example 806

Intermediate I-9 (8.77 mg, 0.029 mmol) and Intermediate 806C (0.008 g,0.029 mmol) were dissolved in DMF (0.292 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(1.432 mg, 1.753 μmol) was added, and the reaction mixture was degassedby bubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution(0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassedfor 5 minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was filtered and purified by preparativeHPLC (Method D, 20 to 100% B in 20 minutes) to yield Example 806 (0.0032g, 0.007 mmol, 24% % yield): ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s, 1H),8.55 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.84 (s, 1H), 7.32 (d, J=10.4 Hz,1H), 5.46 (br. s., 1H), 4.07 (s, 3H), 2.64 (s, 3H), 0.95 (s, 9H). LC-MS:method H, RT=1.39 min, MS (ESI) m/z: 412.2 (M+H)⁺. Analytical HPLCMethod B: 92% purity.

Example 8071-(5-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-7-yl)-2,2-dimethylpropan-1-ol

Intermediate 807A:2-bromo-7-(dibromomethyl)-5-methoxythiazolo[5,4-b]pyridine

Intermediate I-16 (0.250 g, 0.965 mmol) was dissolved in CCl₄ (3 mL) andNBS (0.859 g, 4.82 mmol) was added followed by AIBN (0.048 g, 0.289mmol). The reaction mixture was allowed to stir at reflux for 12 hours.The reaction mixture was cooled and diluted with water and EtOAc. Thelayers were separated and the organic layer was washed with 1 N HCl,washed with brine, dried with sodium sulfate, and concentrated underreduced pressure to yield Intermediate 807A (0.125 g, 0.300 mmol, 31%)which was used without purification. LC-MS: method H, RT=1.14 min, MS(ESI) m/z: 416.9 (M+H)⁺.

Intermediate 807B:1-(2-bromo-5-methoxythiazolo[5,4-b]pyridin-7-yl)-2,2-dimethylpropan-1-ol

Intermediate 807A (0.125 g, 0.458 mmol) was dissolved in THF (4.58 ml)and t-butyl magnesium chloride (0.267 g, 2.288 mmol) was added at −78°C. The reaction mixture was allowed to slowly warm to room temperature.The reaction was quenched with saturated aqueous NH₄Cl and the reactionmixture was diluted with EtOAc. The layers were separated, and theorganic layer was washed with brine, dried with sodium sulfate, andconcentrated under reduced pressure to yield Intermediate 807B (0.034 g,0.103 mmol, 22.43% yield): ¹H NMR (400 MHz, CDCl₃) δ 6.72 (s, 1H), 4.78(d, J=8.1 Hz, 1H), 3.98 (s, 3H), 3.79 (d, J=8.4 Hz, 1H), 0.96 (s, 9H).LC-MS: method H, RT=1.18 min, MS (ESI) m/z: 331.0 (M+H)⁺.

Example 807

Intermediate I-9 (0.034 g, 0.115 mmol) and Intermediate 806B (0.038 g,0.115 mmol) were dissolved in DMF (1.147 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(5.62 mg, 6.88 μmol) was added, and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100ml, 0.300 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was filtered and purified by preparativeHPLC (Method D, 60 to 100% B in 17 minutes) to yield Example 807 (13.7mg, 0.032 mmol, 27.8% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (s, 1H),8.52 (s, 1H), 7.84 (s, 1H), 6.95 (s, 1H), 5.53 (d, J=4.6 Hz, 1H), 5.32(d, J=4.6 Hz, 1H), 4.09 (s, 3H), 3.99 (s, 3H), 2.65 (s, 3H), 0.97 (s,9H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z: 425.1 (M+H)⁺.Analytical HPLC Method B: 99% purity.

Example 8086-methoxy-2-(2-methoxy-7-methylquinoxalin-5-yl)-4-(methoxymethyl)benzo[d]thiazole

Intermediate 808A: 2-bromo-6-methoxy-4-(methoxymethyl)benzo[d]thiazole

Intermediate I-20D (0.100 g, 0.365 mmol) was dissolved in THF (3.65 ml)and sodium hydride (0.022 g, 0.547 mmol) was added. The reaction mixturewas allowed to stir for 10 min and MeI (0.034 ml, 0.547 mmol) was added.The reaction mixture was allowed to stir at room temperature for 3 h.The reaction mixture was diluted with water and EtOAc. The layers wereseparated, and the organic layer was washed with brine, dried withsodium sulfate, and concentrated under reduced pressure. The crudereaction mixture was purified on ISCO using a 12 g column eluting with0-100% EtOAc in hexanes to yield Intermediate 808A (0.037 g, 0.129 mmol,35.5% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.20 (s, 2H),4.96 (s, 2H), 3.90 (s, 3H), 3.53 (s, 3H). LC-MS: method H, RT=1.28 min,MS (ESI) m/z: 287.9 (M+H)⁺.

Example 808

Intermediate I-9 (10 mg, 0.033 mmol) and Intermediate 808A (8.12 mg,0.033 mmol) were dissolved in DMF (0.333 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(1.632 mg, 1.999 μmol) was added, and the reaction mixture was degassedby bubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution(0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassedfor 5 minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was filtered and purified by preparativeHPLC (Method D, 70 to 100% B in 25 minutes) to yield Example 808 (0.0046g, 0.012 mmol, 36% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H),8.58 (s, 1H), 7.83 (s, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.14 (s, 1H), 5.04(s, 2H), 4.09 (s, 3H), 3.89 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H). LC-MS:method H, RT=1.31 min, MS (ESI) m/z: 382.12 (M+H)⁺. Analytical HPLCMethod B: 100% purity.

Example 809 2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[4,5-c]pyridine

Intermediate 809A: 2-chlorothiazolo[4,5-c]pyridine

Copper(II) chloride (0.445 g, 3.31 mmol) and t-butyl nitrite (0.669 ml,5.62 mmol) were dissolved in MeCN (13.23 ml) and allowed to stir 10minutes. Thiazolo[4,5-c]pyridin-2-amine (0.500 g, 3.31 mmol) wasdissolved in MeCN (19.84 ml) and the copper solution was added. Thereaction mixture was stirred for 1.5 h at 60° C. The reaction mixturewas diluted with EtOAc and water. The layers were separated, and theorganic layer was washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purified on ISCO using a 40 g column with 0-100%gradient of EtOAc in hexanes to yield Intermediate 809A (0.125 g, 0.733mmol, 22.15% yield). LC-MS: method H, RT=0.51 min, MS (ESI) m/z: 170.9(M+H)⁺.

Example 809

Intermediate I-9 (17.59 mg, 0.059 mmol) and Intermediate 809A (10 mg,0.059 mmol) were dissolved in DMF (0.586 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(2.87 mg, 3.52 μmol) was added, and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100ml, 0.300 mmol) was added, and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was filtered and purified by preparativeHPLC (Method D, 20 to 25% B in 25 minutes) to yield Example 809 (1.3 mg,4.22 μmol, 7.19% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (br. s., 1H),8.77 (s, 1H), 8.69 (s, 1H), 8.61 (br. s., 1H), 8.41 (br. s., 1H), 7.95(s, 1H), 4.10 (s, 3H), 2.67 (s, 3H). LC-MS: method H, RT=0.86 min, MS(ESI) m/z: 309.1 (M+H)⁺. Analytical HPLC Method B: 100% purity.

Example 8102-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethylpyridin-3-ylcarbamate

Intermediate 810A:2-((2-amino-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate

Intermediate I-131A (1.394 g, 4.02 mmol) was dissolved in DMF (40.2 ml)and Cs₂CO₃ (7.85 g, 24.10 mmol) was added followed by 2-bromoethylacetate (0.805 g, 4.82 mmol). The reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was then heated to 40° C.and allow to stir for 12 hours. The reaction mixture was diluted withwater and EtOAc. The layers were separated, and the organic layer waswashed with brine, dried with sodium sulfate, and concentrated underreduced pressure to yield Intermediate 810A (0.540 g, 1.991 mmol, 49.6%yield). ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J=10.6 Hz, 1H), 5.16 (br. s.,2H), 4.64-4.57 (m, 2H), 4.50-4.42 (m, 2H), 2.09 (s, 3H). LC-MS: methodH, RT=0.69 min, MS (ESI) m/z: 272.1 (M+H)⁺.

Intermediate 810B:2-((2-chloro-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate

Copper(II) chloride (0.455 g, 3.38 mmol) and t-butyl nitrite (0.403 ml,3.38 mmol) were dissolved in MeCN (7.96 ml) and the mixture was allowedto stir for 10 minutes. Intermediate 810A (0.540 g, 1.991 mmol) wasdissolved in MeCN (11.94 ml), and the copper solution was added. Thereaction mixture was stirred for 2.5 hours at 60° C. The reactionmixture was diluted with EtOAc and water. The layers were separated, andthe organic layer was washed with 1 N HCl, washed with saturated aqueousNaHCO₃, washed with brine, dried (Na₂SO₄), filtered, and concentrated invacuo. Purified on ISCO using a 12 g column with 0-100% gradient ofEtOAc in hexanes to yield Intermediate 810B (0.306 g, 1.053 mmol, 52.9%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J=9.7 Hz,1H), 4.71-4.64 (m, 2H), 4.52-4.45 (m, 2H), 2.10 (s, 3H). LC-MS: methodH, RT=1.01 min, MS (ESI) m/z: 291.0 (M+H)⁺.

Intermediate 810C:2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethylacetate

Intermediate I-9 (20.65 mg, 0.069 mmol) and Intermediate 810B (20 mg,0.069 mmol) were dissolved in DMF (0.688 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(3.37 mg, 4.13 μmol) was added, and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100ml, 0.300 mmol) was added, and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. Purified on ISCO using a 12 g column eluting with 0-100% EtOAcin DCM to yield Intermediate 810C (0.039 g, 0.055 mmol, 79% yield) as ayellow solid. LC-MS: method H, RT=1.28 min, MS (ESI) m/z: 428.9 (M+H)⁺.

Intermediate 810D:2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethanol

To a suspension of Intermediate 810C (0.039 g, 0.091 mmol) in THF (1 mL)and MeOH (0.333 mL) was added NaOH (0.273 mL, 0.273 mmol) at roomtemperature. The mixture was stirred at room temperature for 1 hour. Themixture was diluted by EtOAc and 1N HCl. The layers were separated, andthe organic layer was washed with water, washed with brine, dried withsodium sulfate, and concentrated to yield Intermediate 810D (0.050 g,0.129 mmol, 100% yield) as a white solid. Used without furtherpurification in the next step. LC-MS: method H, RT=1.14 min, MS (ESI)m/z: 386.9 (M+H)⁺.

Intermediate 810E:2-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethylcarbonochloridate

To a solution of Intermediate 810D (0.050 g, 0.129 mmol) in THF (5 mL)at room temperature was added 15% phosgene in toluene (0.456 mL, 0.647mmol), and the mixture was stirred for 3 h. Solvent was completelyremoved to yield Intermediate 810E (0.058 g, 0.129 mmol, 100% yield) asa yellow solid. The material was used immediately in the next stepwithout purification. LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 448.8(M+H)⁺.

Example 810

Pyridin-3-amine (0.012 g, 0.129 mmol) and pyridine (0.105 mL, 1.292mmol) were dissolved in DCM (2 mL). Intermediate 810E (0.058 g, 0.129mmol) was added as a solution in DCM (1 mL). The reaction mixture wasallowed to stir for 30 min. The reaction mixture was concentrated underreduced pressure and purified on ISCO using 0-100% EtOAc in hexanes on a12 g column. The reaction mixture was further purified by preparativeHPLC (Method D, 35 to 75% B in 25 minutes, 4 min hold time at 75%) toyield Example 810 (0.0052 g, 10.06 μmol, 7.79% yield) as a pale yellowsolid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.00 (s, 1H), 8.73 (s, 1H), 8.62(br. s., 1H), 8.56 (s, 1H), 8.46 (s, 1H), 8.20 (br. s., 1H), 7.88 (br.s., 2H), 7.33 (br. s., 1H), 4.79 (br. s., 2H), 4.57 (br. s., 2H), 4.10(s, 3H), 2.64 (br. s., 3H). LC-MS: method H, RT=0.98 min, MS (ESI) m/z:507.1 (M+H)⁺. Analytical HPLC Method B: 98% purity.

Example 8112-((6-fluoro-2-(2-methoxy-7-methylquinoxalin-5-yl)thiazolo[5,4-b]pyridin-5-yl)oxy)ethyl (6-fluoro-5-methylpyridin-3-yl)carbamate

To a solution of Intermediate 810E (7.5 mg, 0.017 mmol) in DCM (1 mL)and THF (0.5 mL) was added 6-fluoro-5-methylpyridin-3-amine (7.38 mg,0.058 mmol) followed by DIPEA (0.029 mL, 0.167 mmol). The mixture wasstirred at room temperature for 1 hour. The reaction was quenched with0.2 mL of MeOH. The reaction mixture was concentrated, dissolved in DMF,and filtered. The reaction was purified by preparative HPLC (Method D,50 to 100% B in 20 minutes, 5 min hold time at 100%) to yield Example811 (0.0052 g, 9.37 μmol, 56.1% yield): LC-MS: method H, RT=1.22 min, MS(ESI) m/z: 539.2 (M+H)⁺. Analytical HPLC Method B: 97% purity.

Example 8122-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl (6-(thiophen-2-yl)pyridin-3-yl)carbamate

Intermediate 812A:2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate

2-((2-amino-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate (0.050g, 0.146 mmol) was dissolved in DMF. 2-Bromomethyl acetate (0.058 g,0.350 mmol) and Cs₂CO₃ (0.237 g, 0.729 mmol) were added and the reactionmixture was stirred at 40° C. for 18 h. The reaction mixture was dilutedwith EtOAc and water. The layers were separated. The organic layer waswashed with brine dried with sodium sulfate, and concentrated underreduced pressure. The reaction mixture was purified on ISCO using a 24 gcolumn with a 0-100% EtOAc in hexanes gradient to yield Intermediate812A (0.044 g, 0.165 mmol, 56.5% yield) as a pale yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 6.53-6.53 (m, 1H), 5.01 (br. s., 2H), 4.52-4.48 (m,2H), 4.44-4.39 (m, 2H), 2.49 (d, J=0.7 Hz, 3H), 2.09 (s, 3H). LC-MS:method H, RT=0.72 min, MS (ESI) m/z: 268.2 (M+H)⁺.

Intermediate 812B:2-((2-bromo-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethyl acetate

Copper(II) bromide (0.063 g, 0.280 mmol) and t-butyl nitrite (0.033 mL,0.280 mmol) were dissolved in MeCN (0.658 mL) and allowed to stir 10minutes. Intermediate 812A (0.044 g, 0.165 mmol) was dissolved in MeCN(0.988 mL) and the copper solution was added. The reaction mixture wasdiluted with EtOAc and water. The organic layer was washed with 1 N HCl,washed with saturated aqueous NaHCO₃, washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo to yield Intermediate 812B (0.046 g,0.139 mmol, 84% yield): ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.69 (d, J=0.9Hz, 1H), 4.57-4.53 (m, 2H), 4.44-4.41 (m, 2H), 2.63 (d, J=0.9 Hz, 3H),2.09 (s, 3H). LC-MS: method H, RT=1.07 min, MS (ESI) m/z: 331.0 (M+H)⁺.

Intermediate 812C:2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethylacetate

Intermediate I-9 (0.042 g, 0.140 mmol) and Intermediate 812B (0.046 g,0.140 mmol) were dissolved in DMF (1 mL). PdCl₂(dppf)-CH₂Cl₂Adduct (6.86mg, 8.40 μmol) was added and the reaction mixture was degassed bybubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution (0.100mL, 0.300 mmol) was added and the reaction mixture was degassed for 5minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction was purified on ISCO using 24 g column with a0-100% EtOAc in hexanes gradient to yield Intermediate 812C (0.021 g,0.049 mmol, 35.4% yield) as an off white solid. ¹H NMR (400 MHz, CDCl₃)δ 8.60 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 7.75 (s, 1H), 6.74 (s, 1H), 4.63(dd, J=5.8, 3.6 Hz, 2H), 4.51-4.43 (m, 2H), 4.13 (s, 3H), 2.79 (s, 3H),2.66 (s, 3H), 2.11 (s, 3H). LC-MS: method H, RT=1.34 min, MS (ESI) m/z:425.1 (M+H)⁺.

Intermediate 812D:2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethanol

To a suspension of Intermediate 812C (0.143 g, 0.337 mmol) in THF (3 mL)and MeOH (1 mL) was added NaOH (1.011 mL, 1.011 mmol) at roomtemperature. The mixture was stirred at room temperature for 1 hour. Themixture was diluted with EtOAc and 1N HCl. The organic layer was washedwith water, washed with brine, dried with sodium sulfate, andconcentrated to yield Intermediate 812D (0.120 g, 0.314 mmol, 93% yield)as a tan solid. ¹H NMR (400 MHz, MeOH-d₄) δ 8.61 (s, 1H), 8.58 (s, 1H),7.78 (s, 1H), 6.82 (s, 1H), 4.48-4.45 (m, 2H), 4.40-4.36 (m, 1H), 4.13(s, 3H), 3.94-3.90 (m, 2H), 2.77 (s, 3H), 2.66 (s, 3H). LC-MS: method H,RT=1.15 min, MS (ESI) m/z: 383.9 (M+H)⁺.

Intermediate 812E:2-((2-(2-methoxy-7-methylquinoxalin-5-yl)-7-methylthiazolo[5,4-b]pyridin-5-yl)oxy)ethylcarbonochloridate

To a solution of Intermediate 812D (0.025 g, 0.065 mmol) in THF (3 mL)at was added 15% phosgene in toluene (0.231 mL, 0.327 mmol) and themixture was stirred at for 1 h. The reaction mixture was concentratedunder vacuum to give Intermediate 812E (0.030 g, 0.067 mmol, 100% yield)as a yellow solid. It was used for the next step without anypurification. LC-MS: method H, RT=1.35 min, MS (ESI) m/z: 444.7 (M+H)⁺.

Example 812

To a solution of Intermediate 812E (20 mg, 0.045 mmol) in DCM (1 mL) andTHF (0.5 mL) was added 6-(thiophen-2-yl)pyridin-3-amine (14.81 mg, 0.157mmol) followed by DIEA (0.079 mL, 0.450 mmol). The mixture was stirredat for 1 hour. The reaction mixture was diluted with EtOAc and water.The combined organic layer was washed with brine and concentrated undervacuum. The reaction mixture was diluted with DMSO, filtered, andpurified by preparative HPLC (Method D, 55% to 100% B in 20 minutes) toyield Example 812 (0.0057 g, 5.61 μmol, 12.48% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 10.05 (br. s., 1H), 8.63 (s, 1H), 8.56 (br. s., 1H), 8.50 (s,1H), 7.92 (br. s., 1H), 7.83 (d, J=8.8 Hz, 1H), 7.78 (s, 1H), 7.63 (d,J=3.3 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.12 (t, J=3.9 Hz, 1H), 6.90 (s,1H), 4.66 (br. s., 2H), 4.52 (br. s., 2H), 4.06 (s, 3H), 2.72 (s, 3H),2.62 (s, 3H). LC-MS: method H, RT=1.21 min, MS (ESI) m/z: 585.5 (M+H)⁺.Analytical HPLC Method B: 97% purity.

Example 813(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate 813A:(R)-1-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol

Intermediate I-1(0.483 g, 1.903 mmol) and Intermediate I-131 (0.500 g,1.903 mmol) were dissolved in DMF (19.03 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(0.093 g, 0.114 mmol) was added, and the reaction mixture was degassedby bubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution(0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassedfor 5 minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was diluted with water and EtOAc. Thelayers were separated and the organic layer was washed with brine, driedwith sodium sulfate, and concentrated under reduced pressure to yield abrown oil. Purified by ISCO using 0-70% gradient of EtOAc in hexanes ona 120 g column over 15 min to yield Intermediate 813A (0.591 g, 1.354mmol, 71.1% yield): ¹H NMR (500 MHz, CDCl₃) δ 8.74 (d, J=1.7 Hz, 1H),8.71 (s, 1H), 8.04 (d, J=10.2 Hz, 1H), 7.84 (dd, J=1.8, 1.0 Hz, 1H),7.83-7.53 (m, 1H), 4.58 (dd, J=10.7, 2.8 Hz, 1H), 4.47-4.37 (m, 1H),4.34 (br. s., 1H), 2.71 (s, 3H), 1.61-1.53 (m, 1H), 1.38 (d, J=6.3 Hz,3H). LC-MS: method H, RT=1.24 min, MS (ESI) m/z: 437.1 (M+H)⁺.

Intermediate 813B:(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ol

Intermediate 813A (0.035 g, 0.080 mmol) was dissolved in THF (2 ml) andsodium ethoxide (0.040 ml, 0.080 mmol, 2 M in EtOH) was added. Thereaction mixture was allowed to stir at for 2 hours. The reactionmixture was diluted with water and EtOAc. The layers were separated, andthe organic layer was washed with brine, dried with sodium sulfate, andconcentrated under reduced pressure to yield Intermediate 813B (0.030 g,0.058 mmol, 80% yield). Used without further purification in the nextstep. LC-MS: method H, RT=1.30 min, MS (ESI) m/z: 415.1 (M+H)⁺.

Intermediate 813C:(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-ylcarbonochloridate

To a solution of Intermediate 813B (0.030 g, 0.058 mmol) in THF (3 mL)at was added 15% phosgene in toluene (0.511 mL, 0.724 mmol), and themixture was stirred at for 12 hours. Solvent was completely removed, andthe sample was stored under vacuum overnight to yield Intermediate 813C(0.035 g, 0.066 mmol, 91% yield) as a yellow solid. LC-MS: method H,RT=1.42 min, MS (ESI) m/z: 477.1 (M+H)⁺.

Example 813

2-Methylpyrimidin-5-amine (13.73 mg, 0.126 mmol) and pyridine (0.068 mL,0.839 mmol) were dissolved in DCM (3 mL). Intermediate 813C (40 mg,0.084 mmol) was added as a solution in DCM (1 mL). The reaction mixturewas allowed to stir for 1 hour. The reaction mixture was concentratedunder reduced pressure and purified by ISCO using a 12 g column with a0-100% EtOAc in hexanes gradient to yield Example 813 (0.0203 g, 0.035mmol, 41.8% yield) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 8.74 (br.s., 2H), 8.55 (t, J=2.3 Hz, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.01 (s, 1H),7.98 (d, J=0.9 Hz, 1H), 7.74 (s, 1H), 6.55 (br. s., 1H), 5.75 (dd,J=6.5, 3.4 Hz, 1H), 5.39 (dd, J=6.5, 3.4 Hz, 1H), 4.57 (d, J=7.0 Hz,3H), 2.64 (s, 3H), 1.52 (d, J=1.5 Hz, 3H), 1.50 (s, 3H), 1.48 (d, J=1.5Hz, 3H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 550.1 (M+H)⁺.Analytical HPLC Method B: 95% purity.

Example 814(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate

Intermediate 814A:(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl(2-(2-hydroxyethoxy)pyrimidin-5-yl)carbamate

Intermediate I-97 (16.95 mg, 0.063 mmol) and pyridine (0.034 mL, 0.419mmol) were dissolved in DCM (3 mL). Intermediate 813C (20 mg, 0.042mmol) was added as a solution in DCM (1 mL). The reaction mixture wasallowed to stir for 1 hour. The reaction mixture was concentrated underreduced pressure. Used without further purification in the next step.LC-MS: method H, RT=1.56 min, MS (ESI) m/z: 710.3 (M+H)⁺.

Example 814

Intermediate 814A (0.009 g, 0.013 mmol) was dissolved in THF (2 mL) and2 mL of 90% MeOH, 10% water, 0.1% TFA was added. The reaction mixturewas allowed to stir for 12 hours. The reaction mixture was concentrated,dissolved in DMF, filtered, and purified by preparative HPLC (Method D,50% to 100% B in 19 minutes, 6 min hold time) to yield Example 814 (7.7mg, 0.013 mmol, 100% yield): ¹H NMR (500 MHz, DMSO-d₆) δ 9.81-9.74 (m,1H), 8.61-8.52 (m, 3H), 8.41 (br. s., 1H), 8.33 (d, J=10.7 Hz, 1H), 7.71(s, 1H), 5.67 (br. s., 1H), 5.24 (br. s., 1H), 4.93-4.87 (m, 1H), 4.80(d, J=9.8 Hz, 1H), 4.48 (q, J=6.8 Hz, 5H), 4.20 (d, J=5.2 Hz, 3H), 2.57(s, 3H), 1.45-1.38 (m, 6H). LC-MS: method H, RT=1.20 min, MS (ESI) m/z:596.2 (M+H)⁺. Analytical HPLC Method B: 100% purity.

Example 815(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl (2-(((R)-2-hydroxypropoxy)pyrimidin-5-yl)carbamate

Intermediate 815A:(R)-1-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)propan-2-yl(2-(((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)pyrimidin-5-yl)carbamate

Intermediate I-103 (0.020 g, 0.069 mmol) and pyridine (0.051 mL, 0.629mmol) were dissolved in DCM (2 mL) Intermediate 813C (0.030 g, 0.063mmol) was added as a solution in DCM (1 mL). The reaction mixture wasallowed to stir for 1 hour. The reaction mixture was concentrated underreduced pressure and purified on ISCO using 24 g column eluting with0-100% EtOAc in hexanes over 15 min to yield Intermediate 815A (28.3 mg,0.039 mmol, 62.1% yield) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 9.08-9.05 (m, 2H), 8.56 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.01 (d,J=10.3 Hz, 1H), 7.77 (s, 1H), 6.80 (s, 1H), 5.87-5.73 (m, 1H), 5.28 (dd,J=6.6, 2.9 Hz, 1H), 4.68-4.54 (m, 1H), 4.09 (s, 2H), 2.67 (s, 3H),1.54-1.48 (m, 9H). LC-MS: method H, RT=1.58 min, MS (ESI) m/z: 724.0(M+H)⁺.

Example 815

Intermediate 815A (0.0283 g, 0.039 mmol) was dissolved in THF (1 mL) andEtOH (1 mL). To the solution was added 4 M HCl in dioxane (1 mL, 110mmol), and the reaction mixture was allowed to stir at room temperaturefor 3 hours. The reaction mixture was concentrated under reducedpressure, dissolved in DMF, filtered, and purified by preparative HPLC(Method D, 50% to 100% B in 20 minutes, 10 min hold time) to yieldExample 815 (0.0145 g, 0.024 mmol, 60.8% yield): ¹H NMR (500 MHz,DMSO-d₆) δ 9.86-9.73 (m, 1H), 8.62-8.53 (m, 3H), 8.44 (br. s., 1H), 8.36(d, J=10.7 Hz, 1H), 7.74 (s, 1H), 5.69 (br. s., 1H), 5.26 (br. s., 2H),4.83 (d, J=10.1 Hz, 1H), 4.50 (q, J=7.0 Hz, 4H), 4.29 (d, J=7.6 Hz, 1H),4.04 (d, J=12.8 Hz, 1H), 3.93 (br. s., 1H), 3.52-3.46 (m, 3H), 2.59 (s,3H), 1.47-1.40 (m, 6H). LC-MS: method H, RT=1.23 min, MS (ESI) m/z:610.1 (M+H)⁺. Analytical HPLC Method B: 100% purity.

Example 816(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl(2-(hydroxymethyl)pyrimidin-5-yl)carbamate

Intermediate 816A:(2R,3S)-3-((2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol

Intermediate I-1(0.075 g, 0.285 mmol) and Intermediate I-133 (0.082 g,0.285 mmol) were dissolved in DMF (2.95 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(0.012 g, 0.018 mmol) was added, and the reaction mixture was degassedby bubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution(0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassedfor 5 minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was diluted with water and EtOAc. Thelayers were separated and the organic layer was washed with brine, driedwith sodium sulfate, and concentrated under reduced pressure to yield abrown oil. Purified by ISCO using 0-100% gradient of EtOAc in hexanes ona 24 g column over 15 min to yield Intermediate 816A (0.050 g, 0.111mmol, 37.6% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.74 (d, J=1.8 Hz, 1H),8.71 (s, 1H), 8.03 (d, J=10.1 Hz, 1H), 7.89-7.49 (m, 2H), 5.41 (dd,J=6.5, 3.0 Hz, 1H), 4.26-4.08 (m, 1H), 2.49 (d, J=4.6 Hz, 1H), 1.46 (d,J=6.4 Hz, 3H), 1.33 (d, J=6.4 Hz, 3H). LC-MS: method H, RT=1.27 min, MS(ESI) m/z: 451.1 (M+H)⁺.

Intermediate 816B:(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ol

Intermediate 816A (0.100 g, 0.222 mmol) was dissolved in THF (2 ml) andsodium ethoxide (0.111 ml, 0.222 mmol, 2 M in EtOH) was added. Thereaction mixture was allowed to stir at room temperature for 2 hours.The reaction mixture was diluted with water and EtOAc. The layers wereseparated, and the organic layer was washed with brine, dried withsodium sulfate, and concentrated under reduced pressure to yieldIntermediate 816B (0.090 g, 0.210 mmol, 95% yield). Used without furtherpurification in the next step. LC-MS: method H, RT=1.25 min, MS (ESI)m/z: 429.1 (M+H)⁺.

Intermediate 816C:(2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-ylcarbonochloridate

To a solution of Intermediate 816B (0.025 g, 0.058 mmol) in THF (5 mL)at room temperature was added 15% phosgene in toluene (0.206 mL, 0.292mmol), and the mixture was stirred at room temperature for 12 hours.Solvent was completely removed, and the sample was stored under vacuumovernight to yield Intermediate 816C (0.029 g, 0.053 mmol, 90% yield) asa yellow solid. LC-MS: method H, RT=1.43 min, MS (ESI) m/z: 490.0(M+H)⁺.

Intermediate 816D: methyl5-(((((2R,3S)-3-((2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-fluorothiazolo[5,4-b]pyridin-5-yl)oxy)butan-2-yl)oxy)carbonyl)amino)pyrimidine-2-carboxylate

Methyl 5-aminopyrimidine-2-carboxylate (10.29 mg, 0.067 mmol) andpyridine (0.049 mL, 0.611 mmol) were dissolved in DCM (2 mL)Intermediate 816C (0.030 g, 0.061 mmol) was added as a solution in DCM(1 mL). The reaction mixture was allowed to stir for 1 hour. Thereaction mixture was concentrated under reduced pressure and purified onISCO using 24 g column eluting with 0-100% EtOAc over 15 min to yieldIntermediate 816D (24.6 mg, 0.040 mmol, 66.3% yield) as a pale yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=1.8 Hz, 3H), 8.44 (s, 1H),7.91 (d, J=10.3 Hz, 1H), 7.66 (s, 1H), 7.13 (s, 1H), 5.70-5.60 (m, 1H),5.31 (br. s., 1H), 2.56 (s, 3H), 1.41 (d, J=6.8 Hz, 5H), 1.17 (s, 3H),0.07-0.11 (m, 6H). LC-MS: method H, RT=1.27 min, MS (ESI) m/z: 608.0(M+H)⁺.

Example 816

Intermediate 816D (39 mg, 0.064 mmol) was solvated in THF (1 mL) andcooled to −78° C. Diisobutylaluminum hydride (1 M in toluene) (0.193 mL,0.193 mmol) was added to the cooled mixture, and the reaction mixturewas stirred for 30 min. The reaction mixture was quenched with 1 mL of a1 M HCl solution at −78° C. The resulting thick, orange sludge wasallowed to thaw to room temperature and stirred for a total of 30 minuntil the solution became fluid and bright yellow. The mixture wasdiluted with EtOAc and washed with saturated NH₄Cl before being driedover sodium sulfate and filtered over a pad of SiO₂ gel to removealuminates. The filtrate was concentrated and resubjected to identicalreaction conditions to those described above. This second reactionmixture was quenched with saturated Rochelle's salt and allowed to stirat room temperature for 1 hour. The resulting mixture was diluted withEtOAc and the layers were separated. The aqueous layer was backextracted with EtOAc 3×, and the combined organic layer was washed withbrine, dried with sodium sulfate, and concentrated under reducedpressure. The crude material was dissolved in DMF, filtered, andpurified by preparative HPLC (Method D, 50% to 100% B in 22 minutes, 5min hold time) to yield Example 816 (0.0078 g, 0.013 mmol, 20.97%yield): ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br. s., 1H), 8.79 (br. s.,2H), 8.61 (s, 1H), 8.49 (s, 1H), 8.41 (d, J=10.7 Hz, 1H), 7.79 (s, 1H),5.68 (d, J=6.4 Hz, 1H), 5.17 (d, J=5.2 Hz, 1H), 4.53 (q, J=7.0 Hz, 2H),4.49 (s, 2H), 2.61 (s, 3H), 1.47-1.43 (m, 6H), 1.40 (d, J=6.4 Hz, 3H).LC-MS: method H, RT=0.98 min, MS (ESI) m/z: 580.0 (M+H)⁺. AnalyticalHPLC Method B: 100% purity.

Example 8171-(2-(2-ethoxy-7-methylquinoxalin-5-yl)-6-methoxybenzo[d]thiazol-4-yl)-2,2-dimethylpropan-1-ol

Intermediate 817A:2-ethoxy-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline

In a sealed tube, Intermediate 661F (290 mg, 1.086 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (551 mg,2.171 mmol), and potassium acetate (213 mg, 2.171 mmol) were mixed in1,4-dioxane (5 mL). After degassing with bubbling argon for 10 minutes,Pd(dppf)Cl₂.CH₂Cl₂ (44.3 mg, 0.054 mmol) was added. The vial was sealedand heated at 120° C. for 60 minutes in the microwave. The reactionmixture was cooled to room temperature, loaded on celite and waspurified on ISCO (40 g column, 0-50% EtOAc/Hexane in 18 minutes) toyield Intermediate 817A (0.311 g, 0.990 mmol, 91% yield): ¹H NMR (400MHz, DMSO-d₆) δ 8.53 (s, 1H), 7.91 (s, 1H), 7.68 (s, 1H), 4.47 (q, J=7.2Hz, 2H), 3.26 (br. s., 3H), 1.41 (t, J=7.0 Hz, 3H), 1.34 (s, 12H).LC-MS: method H, RT=0.94 min, MS (ESI) m/z: 233.0 (M+H)⁺ (mass of theboronic acid).

Example 817

Intermediate 817A (10 mg, 0.032 mmol) and Intermediate 628A (9.10 mg,0.032 mmol) were dissolved in DMF (1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(1.560 mg, 1.910 μmol) was added, and the reaction mixture was degassedby bubbling with argon for 15 minutes. Na₂CO₃, 3 M aqueous solution(0.100 ml, 0.300 mmol) was added, and the reaction mixture was degassedfor 5 minutes, then sealed and heated to 90° C. in the microwave for 30minutes. The reaction mixture was filtered and purified by preparativeHPLC (Method D, 45% to 80% B in 25 minutes, 7 min hold time) to yieldExample 817 (4.5 mg, 9.87 μmol, 31.0% yield): ¹H NMR (500 MHz, DMSO-d₆)δ 8.68 (s, 1H), 8.51 (s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.13 (s, 1H),5.41 (d, J=4.6 Hz, 1H), 5.36 (br. s., 1H), 4.53 (q, J=7.0 Hz, 2H), 3.86(s, 3H), 2.63 (s, 3H), 1.44 (t, J=7.0 Hz, 3H), 0.94 (s, 9H). LC-MS:method H, RT=1.39 min, MS (ESI) m/z: 438.2 (M+H)⁺. Analytical HPLCMethod B: 96% purity.

Example 818(R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl(6-cyanopyridin-3-yl)carbamate

Intermediate 818A(R)-1-((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-ol

In a flask charged with a stirring bar, Intermediate I-60 (215 mg, 0.867mmol) was suspended in (R)-2-methyloxirane (1 mL, 0.867 mmol). Potassiumcarbonate (144 mg, 1.040 mmol) was added, followed by tetrabutylammoniumbromide (335 mg, 1.040 mmol). The mixture was allowed to stir at 60° C.for 18 hours. On the next day, the reaction mixture was diluted byadding 20 mL of DCM and silica gel was added. The solvent was removed onthe rotavapor and sample was dry loaded on ISCO (24 g silica gel column,0-60% EtOAc/Hexane). Collection of the desired fraction and removal ofsolvent gave Intermediate 818A (245.4 mg, 0.802 mmol, 92% yield) ascolorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (d, J=1.3 Hz, 1H),7.97-7.89 (m, 1H), 4.96 (d, J=4.8 Hz, 1H), 4.07-3.98 (m, 1H), 3.98-3.89(m, 2H), 1.18 (d, J=6.2 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −133.79(s, 1F); LC-MS: method E, RT=0.85 min, MS (ESI) m/z: 306.0, 308.0(M+H)⁺.

Intermediate 818B:(R)-1-((2-bromo-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-ylcarbonochloridate

Intermediate 818A (110 mg, 0.359 mmol) was dissolved in THF (5 mL) underN₂. Phosgene (2.56 mL, 3.59 mmol, 15% by wt.) in toluene solution wasadded. The resulting mixture was stirred at room temperature for 5hours, then the solvent was removed on rotavapor and residue was driedon HVAC for 30 minutes. The crude product was used in the next stepwithout purification. LC-MS: method E, RT=1.08 min, MS (ESI) m/z: 365.0,366.9 (M+H)⁺.

Intermediate 818C:(R)-1-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl(6-cyanopyridin-3-yl)carbamate

Intermediate 818B (66 mg, 0.179 mmol) was dissolved in DCM (3 mL) andmixed with 5-aminopicolinonitrile (85 mg, 0.716 mmol). Anhydrouspyridine (0.072 mL, 0.895 mmol) was added. The mixture was allowed tostir at room temperature for 2 hours. The solvent was removed onrotavapor and the residue was purified on ISCO column (24 g silica gel,0-100% EtOAc/Hexane). The desired fractions were collected and removingsolvent gave Intermediate 818C (59 mg, 0.145 mmol, 81% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.75 (d, J=2.6 Hz,1H), 8.08 (dd, 2.5 Hz, 1H), 8.01-7.87 (m, 3H), 5.26 (td, J=6.4, 3.1 Hz,1H), 4.37-4.32 (m, 1H), 4.23 (dd, J=11.0, 6.2 Hz, 1H), 1.41 (d, J=6.6Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −133.72 (s, 1F); LC-MS: method E,RT=0.97 min, MS (ESI) m/z: 407.0 (M+H)⁺.

Example 818

In a vial charged with a stirring bar, Intermediate 818C (14 mg, 0.034mmol) was mixed with Intermediate I-38 (12.7 mg, 0.041 mmol) in1,4-dioxane (1 mL). PdCl₂(dppf)-DCM (2.81 mg, 3.44 μmol) was added,followed by Na₂CO₃ (0.5 ml, 1.0 mmol). The reaction mixture was allowedto stir at 100° C. for 30 minutes. After cooling down to roomtemperature, the layers were separated and the aqueous layer wasextracted by EtOAc (2 mL×2). Then organic phases were combined andconcentrated on Rotavapor. The residue was dissolved in DMF and purifiedby prep-HPLC, Method B to afford Example 818 (3.8 mg, 0.007 mmol, 20%yield) as the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (s, 1H),8.81 (s, 1H), 8.74 (s, 1H), 8.51 (s, 1H), 8.08 (d, J=8.2 Hz, 1H),8.03-7.90 (m, 3H), 5.29 (br. s., 1H), 4.40 (d, J=8.5 Hz, 1H), 4.29 (dd,J=10.7, 5.8 Hz, 1H), 4.11 (s, 3H), 3.35 (s, 1H), 1.44 (d, J=6.4 Hz, 3H);LC-MS: method L, RT=2.26 min, MS (ESI) m/z: 556.15 (M+H)⁺.

Example 819(R)-1-((2-(7-cyano-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate 819A:(R)-1-((2-chloro-5-fluorobenzo[d]thiazol-6-yl)oxy)propan-2-yl(2-methylpyrimidin-5-yl)carbamate

Intermediate 819A was synthesized by the method described inIntermediate 818C, using 2-methylpyrimidin-5-amine instead of5-aminopicolinonitrile. LC-MS: method E, RT=0.86 min, MS (ESI) m/z:397.1 (M+H)⁺.

Example 819

Example 819 (2.2 mg, 0.004 mmol, 16% yield) was made from Intermediate819A (9.0 mg, 0.023 mmol) by the method described for Example 818.LC-MS: method L, RT=2.03 min, MS (ESI) m/z: 546.10 (M+H)⁺.

Example 820(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(2-methoxypyrimidin-5-yl)carbamate

Intermediate 820A:(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ol

In a vial charged with a stirring bar, Intermediate I-72A (228 mg, 0.713mmol) was mixed with Intermediate I-28 (170 mg, 0.713 mmol) in1,4-dioxane (5 mL). Na₂CO₃ (2 mL, 4.00 mmol) was added, followed byPd(dppf)Cl₂-DCM (29.1 mg, 0.036 mmol). The mixture was stirred at 100°C. for 30 min. After cooling down to room temperature, the reactionmixture was diluted by adding 30 mL of EtOAc and 20 mL of water. Afterseparation, the aqueous layer was extracted by EtOAc (20 mL×2). Then theorganic phases were combined and washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified on CombiFlash(40 g silica gel column, 0-100% EtOAc/Hexane). Removing solvent gaveIntermediate 820A (296 mg, 0.682 mmol, 96% yield) as a yellow solid.LC-MS: method E, RT=1.09 min, MS (ESI) m/z: 434.1 (M+H)⁺.

Intermediate 820B:(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-ylcarbonochloridate

Intermediate 820A (0.290 g, 0.668 mmol) was dissolved in anhydrous THF(7 mL) and was treated with phosgene (4.77 mL, 6.68 mmol, 15% by wt. intoluene) at room temperature overnight. On the next day, LCMS showed aclean reaction. Then solvent was removed on the rotavapor and theresidue was dried on high vacuum for 1 hour. The crude product was usedin the next step as is. LC-MS: method E, RT=1.34 min, MS (ESI) m/z:496.1 (M+H)⁺.

Example 820

In a round bottom flask charged with a stirring bar, Intermediate 820B(60 mg, 0.121 mmol) was dissolved in DCM (2 mL) and mixed with2-methoxypyrimidin-5-amine (60.5 mg, 0.484 mmol). Pyridine (0.049 mL,0.604 mmol) was added and the mixture was stirred at room temperaturefor 4 hours. Solvent was removed on a rotavapor and the residue wasloaded on silica gel and purified by CC (40 g silica gel, 0-100%EtOAc/Hexane gradient). The desired fractions were removed andfreeze-dried to give Example 820 (55.8 mg, 0.093 mmol, 77% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.69-9.87 (1H, m), 8.82(1H, s), 8.63 (1H, d, J=2.42 Hz), 8.61 (1H, br. s.), 8.08 (1H, d, J=2.42Hz), 8.06 (1H, d, J=8.14 Hz), 8.00 (1H, d, J=11.44 Hz), 5.09 (1H, dd,J=6.60, 2.64 Hz), 4.82 (1H, dd, J=6.38, 2.86 Hz), 4.10 (3H, s), 3.83(3H, s), 3.57 (1H, s), 1.36-1.42 (6H, m); ¹⁹F NMR (376 MHz, DMSO-d₆) δppm −132.98 (1F, s); LC-MS: method G, RT=1.14 min, MS (ESI) m/z: 585.1(M+H)⁺.

Examples 821 to 830

The following additional examples have been prepared, isolated andcharacterized using the methods described for Example 820 and theexamples above, from corresponded quinoxaline boronic acids and anilineintermediates.

LCMS LCMS [M + RT Ex. H]⁺ (Min)/ No. Structure m/z Method NMR 821

584.15 2.66/L ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.61 (1 H, br. s.), 8.79(1 H, s), 8.58 (1 H, d, J = 1.83 Hz), 8.19 (1 H, br. s.), 8.01-8.06 (2H, m), 7.97 (1 H, d, J = 11.29 Hz), 7.74 (1 H, br. s.), 6.74 (1 H, d, J= 7.63 Hz), 5.07 (1 H, d, J = 4.27 Hz), 4.79 (1 H, d, J = 3.97 Hz), 4.08(3 H, s), 3.76 (3 H, s), 1.38 (6 H, dd, J = 11.14, 6.26 Hz) 822

568.15 2.22/L ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.82 (1 H, br. s.), 8.82(1 H, s), 8.62 (1 H, d, J = 2.44 Hz), 8.50 (1 H, br. s.), 8.04-8.10 (2H, m), 8.00 (1 H, d, J = 11.29 Hz), 7.77 (1 H, br. s.), 7.20 (1 H, br.s.), 5.09 (1 H, d, J = 6.71 Hz), 4.80 (1 H, br. s.), 4.10 (3 H, s), 2.37(3 H, s), 1.33-1.46 (6 H, m)⁾ 823

559.2 1.90/L ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.78 (1 H, br. s.), 8.85 (1H, s), 8.73 (1 H, s), 8.48 (1 H, br. s.), 8.45 (1 H, s), 8.02 (1 H, d, J= 7.93 Hz), 7.92 (1 H, d, J = 11.29 Hz), 7.75 (1 H, br. s.), 7.15 (1 H,d, J = 8.24 Hz), 5.10 (1 H, d, J = 6.41 Hz), 4.79 (1 H, d, J = 3.97 Hz),4.09 (3 H, s), 2.36 (3 H, s), 1.39 (6 H, dd, J = 11.29, 6.41 Hz) 824

569.0 1.26/E ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.93 (1 H, br. s.), 8.84 (1H, s), 8.72 (2 H, br. s.), 8.64 (1 H, d, J = 2.42 Hz), 8.09 (1 H, d, J =2.42 Hz), 8.07 (1 H, d, J = 8.36 Hz), 8.01 (1 H, d, J = 11.44 Hz), 5.11(1 H, dd, J = 6.49, 2.75 Hz), 4.77- 4.93 (1 H, m), 4.10 (3 H, s),2.51-2.52 (3 H, m), 1.39 (6 H, dd, J = 6.49, 3.41 Hz). ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −132.97 (1 F, s) 825

560.2 2.11/L ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.95 (1 H, br. s.), 8.94 (1H, s), 8.84 (1 H, s), 8.71 (2 H, br. s.), 8.53 (1 H, s), 8.06 (1 H, d, J= 8.24 Hz), 7.99 (1 H, d, J = 11.60 Hz), 5.10 (1 H, d, J = 6.41 Hz),4.83 (1 H, d, J = 5.19 Hz), 4.11 (3 H, s), 2.50 (3 H, s), 1.39 (6 H, t,J = 6.26 Hz) 826

579.1 1.15/E ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.26 (1 H, s), 8.83 (1 H,s), 8.81 (1 H, s), 8.64 (1 H, d, J = 2.20 Hz), 8.60 (1 H, s), 8.23 (1 H,br. s.), 8.06-8.12 (2 H, m), 8.01 (1 H, d, J = 11.44 Hz), 5.12 (1 H, d,J = 6.82 Hz), 4.85 (1 H, s), 4.11 (3 H, s), 1.40 (6 H, d, J = 6.60 Hz)¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −132.95 (1 F, s) 827

599.1 0.90/J ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.85-10.06 (1 H, m), 8.80(1 H, s), 8.72 (2 H, br. s.), 8.57 (1 H, s), 8.02 (1 H, d, J = 8.24 Hz),7.93 (1 H, d, J = 11.29 Hz), 7.81 (1 H, s), 6.39- 6.65 (1 H, m), 5.10 (1H, dd, J = 6.56, 2.29 Hz), 4.68-4.89 (3 H, m), 2.61 (3 H, s), 2.54 (3 H,s), 1.38 (6 H, t, J = 5.65 Hz) 828

570.20 2.36/L ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.85 (1 H, s), 8.73 (1 H,s), 8.66 (1 H, br. s.), 8.45 (1 H, s), 8.00 (2 H, d, J = 7.93 Hz),7.82-7.95 (2 H, m), 5.09 (1 H, d, J = 6.41 Hz), 4.81 (1 H, d, J = 4.27Hz), 4.06 (3 H, s), 1.37 (7 H, t, J = 5.34 Hz) 829

579.15 2.69/M ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.40 (1 H, s), 8.66- 8.77(2 H, m), 8.51 (1 H, d, J = 2.14 Hz), 7.85-8.12 (5 H, m), 5.13 (1 H, dd,J = 6.41, 2.14 Hz), 4.84 (1 H, d, J = 3.97 Hz), 4.06 (3 H, s), 1.35-1.45(6H, m) 830

612.2 2.69/G ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (s, 1H), 8.82 (s, 1H),8.70 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.3 Hz, 1H), 8.16-7.83 (m, 5H),5.12 (dd, J = 6.6, 2.6 Hz, 1H), 4.86 (d, J = 6.6 Hz, 1H), 4.10 (s, 3H),3.80 (s, 3H), 1.41 (dd, J = 6.5, 2.8 Hz, 6H)

Example 831(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-(hydroxymethyl)pyridin-3-yl)carbamate

Example 830 (10 mg, 0.016 mmol) was dissolved in anhydrous THF (1 mL)and cooled to −78° C. under an atmosphere of N₂. DIBAL-H (0.082 mL,0.082 mmol) was then added drop wise. After 2 min of stirring at −78°C., the reddish solution was allowed to thaw to room temperature. Next,1 mL of saturated Rochelle's Salt solution was added to quench thereaction, causing the solution to return to a yellow color. The reactionmixture was stirred vigorously for 3 h before being diluted with EtOAcand washed with saturated NH₄Cl (aq.). The organic phase was dried overNa₂SO₄, filtered, concentrated. The crude product was purified byprep-HPLC, Method D to afford Example 831 (2.4 mg, 0.004 mmol, 24%yield) as the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.81 (1H,br. s.), 8.64 (1H, s), 8.50 (1H, br. s.), 8.44 (1H, s), 7.77-8.03 (4H,m), 7.34 (1H, d, J=8.54 Hz), 5.36-5.45 (1H, m), 5.10 (1H, d, J=5.19 Hz),4.76 (1H, br. s.), 4.45 (2H, d, J=5.19 Hz), 4.03 (3H, s), 1.38 (6H, dd,J=12.36, 6.26 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ ppm −132.94 (1F, s.);LC-MS: method L, RT=2.24 min, MS (ESI) m/z: 584.25 (M+H)⁺.

Example 832(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-(methylcarbamoyl)pyridin-3-yl)carbamate

To a vial charged with Example 830 (8 mg, 0.013 mmol) were added THF(0.4 mL), followed by methylamine (0.6 mL, 0.013 mmol). The reactionmixture was sealed and heated at 60° C. for 30 minutes. The solvent wasremoved and the residue was redissolved in DMF, before being purified byprep-HPLC, Method D to afford Example 832 (4.9 mg, 0.008 mmol, 59%yield) as the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.11 (1H,br. s.), 8.61 (1H, br. s.), 8.54 (1H, d, J=4.58 Hz), 8.43 (1H, s),7.61-8.11 (6H, m), 5.11 (1H, d, J=6.10 Hz), 4.83 (1H, d, J=6.10 Hz),4.03 (3H, s), 2.75 (3H, d, J=4.58 Hz), 1.40 (6H, dd, J=8.85, 7.02 Hz);¹⁹F NMR (471 MHz, DMSO-d₆) δ ppm −132.95 (1F, br. s.); LC-MS: method L,RT=2.57 min, MS (ESI) m/z: 611.15 (M+H)⁺.

Example 833(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl (6-carbamoylpyridin-3-yl)carbamate

Example 830 (8 mg, 0.013 mmol) was dissolved in THF (0.5 mL). NH₃ (2 mL,14.00 mmol) in methanol (7N) was added. The reaction mixture was sealedand heated at 60° C. for 20 hours. On the next day, solvent was removedand the residue was purified by prep-HPLC, Method D to afford Example833 (4.5 mg, 0.007 mmol, 55% yield) as the title compound. ¹H NMR (500MHz, DMSO-d₆) δ ppm 10.16 (1H, br. s.), 8.50-8.70 (2H, m), 8.39 (1H, br.s.), 7.75-8.09 (6H, m), 7.43 (1H, br. s.), 5.12 (1H, d, J=6.10 Hz), 4.78(1H, d, J=4.58 Hz), 4.01 (3H, s), 1.33-1.46 (6H, m); ¹⁹F NMR (471 MHz,DMSO-d₆) δ ppm −132.98 (1F, br. s.); LC-MS: method L, RT=2.50 min, MS(ESI) m/z: 597.10 (M+H)⁺.

Example 834(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-(dimethylcarbamoyl)pyridin-3-yl)carbamate

To a vial charged with Example 830 (8 mg, 0.013 mmol) was added THF (0.5mL). The resulting solution was cooled to 0° C. and magnesium chloride(6.22 mg, 0.065 mmol) was added. The mixture was allowed to stir for 30min before dimethylamine (0.196 mL, 0.392 mmol) was added. The ice bathwas allowed to expire and the reaction mixture was stirred at 60° C. for2 hours. After cooling down to room temperature, solvent was removed andthe residue was dissolved in DMF. The remaining solids were removed byfiltration and the resulting solution was purified by prep-HPLC, MethodD to afford Example 834 (0.8 mg, 0.001 mmol, 10% yield) as the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.07 (1H, br. s.), 8.80 (1H,s), 8.60 (2H, d, J=2.48 Hz), 8.03-8.10 (2H, m), 7.92-8.02 (2H, m), 7.52(1H, d, J=8.53 Hz), 5.13 (1H, dd, J=6.60, 2.75 Hz), 4.83 (1H, dd,J=6.33, 2.75 Hz), 4.09 (3H, s), 2.96 (6H, d, J=6.33 Hz), 1.40 (6H, dd,J=6.33, 5.23 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ ppm −138.05 (1F, br. s.);LC-MS: method L, RT=2.52 min, MS (ESI) m/z: 625.15 (M+H)⁺.

Example 835(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-(2-hydroxy-2-methylpropyl)pyridin-3-yl)carbamate

1-(5-aminopyridin-2-yl)-2-methylpropan-2-ol (2.95 mg, 0.018 mmol) wasdissolved in DCM (0.5 mL) and pyridine (1.955 μl, 0.024 mmol) was added.A solution of Intermediate 820B (8 mg, 0.016 mmol) in DCM (0.5 mL) wasadded dropwise to the reaction mixture. The mixture was stirred at roomtemperature overnight. On the next day, solvent was removed and theresidue was purified by prep-HPLC, Method D to afford Example 835 (6.8mg, 0.010 mmol, 63% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.76 (1H,br. s.), 8.65 (1H, s), 8.49 (1H, br. s.), 8.46 (1H, d, J=2.14 Hz), 7.94(1H, d, J=8.24 Hz), 7.92 (1H, d, J=2.14 Hz), 7.87 (1H, d, J=11.60 Hz),7.75 (1H, br. s.), 7.19 (1H, d, J=8.24 Hz), 5.09 (1H, dd, J=6.41, 2.75Hz), 4.77 (1H, dd, J=6.26, 2.59 Hz), 4.04 (3H, s), 3.53 (1H, s), 2.72(2H, s), 1.38 (6H, dd, J=12.66, 6.56 Hz), 1.02 (6H, s); NMR (471 MHz,DMSO-d₆) δ ppm −132.92 (1F, br. s.); LC-MS: method L, RT=2.29 min, MS(ESI) m/z: 626.15 (M+H)⁺.

Example 836(2R,3S)-3-((2-(7-chloro-2-methoxyquinoxalin-5-yl)-5-fluorobenzo[d]thiazol-6-yl)oxy)butan-2-yl(6-(2-hydroxyethyl)pyridin-3-yl)carbamate

Intermediate I-93 (7.83 mg, 0.031 mmol) was dissolved in DCM (0.5 mL)and pyridine (3.42 μl, 0.042 mmol) was added. Then Intermediate 820B (14mg, 0.028 mmol) in DCM (0.5 mL) was added dropwise to the reactionmixture. The mixture was stirred at room temperature overnight. On thenext day, TBAF (0.282 mL, 0.282 mmol) solution was added. After stirringfor 3 hours, HCl (0.071 mL, 0.282 mmol) was added. The reaction mixturewas stirred at room temperature for an additional 30 minutes. Thensolvent was removed on the rotavapor and the residue was purified byprep-HPLC, Method D to afford Example 836 (4.8 mg, 0.008 mmol, 27%yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.75 (1H, br. s.), 8.64 (1H, s),8.49 (1H, br. s.), 8.45 (1H, s), 7.93 (1H, d, J=8.24 Hz), 7.91 (1H, s),7.85 (1H, d, J=11.60 Hz), 7.71-7.79 (1H, m), 7.18 (1H, d, J=8.54 Hz),5.09 (1H, d, J=6.41 Hz), 4.76 (1H, d, J=5.80 Hz), 4.03 (3H, s), 3.66(1H, t, J=6.71 Hz), 3.56 (1H, d, J=2.75 Hz), 2.77 (2H, t, J=6.71 Hz),1.37 (7H, dd, J=13.43, 6.41 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ ppm−132.95 (1F, br. s.); LC-MS: method L, RT=2.19 min, MS (ESI) m/z: 598.15(M+H)⁺.

Example 8372-(7-chloro-2-methoxyquinoxalin-5-yl)-6-methoxy-4-methylbenzo[d]thiazole

In a vial charged with a stirring bar, Intermediate I-28 (17 mg, 0.053mmol) was dissolved in 1,4-dioxane (1 mL), mixed with2-bromo-6-methoxy-4-methylbenzo[d]thiazole (17.80 mg, 0.069 mmol).Na₂CO₃ (1 mL, 2.0 mmol) was added, followed by PdCl₂(dppf)-DCM (4.33 mg,5.30 μmol). The reaction mixture was stirred at 100° C. for 1 hour.After cooling down to room temperature, the reaction mixture was dilutedby adding 20 ml of EtOAc and 20 mL of water. After shaking andseparation, the organic phase was passed through Na₂SO₄ and concentratedon rotavapor. The residue was purified by prep-HPLC, Method D to affordExample 837 (2.0 mg, 0.005 mmol, 10% yield). ¹H NMR (500 MHz, CDCl₃-d) δ8.80 (d, J=2.5 Hz, 1H), 8.59 (s, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.24 (d,J=2.5 Hz, 1H), 6.95 (s, 1H), 4.14 (s, 3H), 3.90 (s, 3H), 2.83 (s, 3H);LC-MS: method L, RT=2.934 min, MS (ESI) m/z: 372.10 (M+H)⁺.

What is claimed is:
 1. A compound of Formula (I) to (VIII):

or a salt thereof; wherein: R₁ is F, Cl, —OH, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, C₃₋₇fluorocycloalkyl, C₁₋₄ alkoxy, C₁₋₄ fluoroalkoxy, C₂₋₄ hydroxyalkoxy,C₃₋₆ cycloalkoxy, (C₁₋₃ alkoxy)-(C₁₋₃ alkylene), (C₁₋₃ alkoxy)-(C₁₋₃fluoroalkylene), (C₁₋₃ deuteroalkoxy)-(C₁₋₃ deuteroalkylene), (C₁₋₃fluoroalkoxy)-(C₁₋₃ alkylene), (C₁₋₃ fluoroalkoxy)-(C₁₋₃fluoroalkylene), —(CH₂)₁₋₃O(phenyl), —(CH₂)₁₋₃NR_(a)R_(a), —C(O)O(C₁₋₆alkyl), —C(O)NR_(a)R_(a), —C(O)NR_(b)R_(b), —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —NH(C₁₋₆ hydroxyalkyl), azetidinyl, pyrrolidinyl,furanyl, pyranyl, piperidinyl, morpholinyl, piperazinyl, —S(O)₂(C₁₋₃alkyl), —S(O)₂NR_(a)R_(a), C₁₋₃ alkylthio, or C₁₋₃ fluoroalkylthio; R₂,at each occurrence, is independently H, F, Cl, Br, —OH, —CN, C₁₋₄ alkyl,C₁₋₄ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃ aminoalkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ fluorocycloalkyl, C₁₋₆ alkoxy, C₁₋₃fluoroalkoxy, C₁₋₃ alkylthio, C₁₋₃ fluoroalkylthio, (C₁₋₃ alkoxy)-(C₁₋₃alkylene), (C₁₋₃ fluoroalkoxy)-(C₁₋₃ alkylene), —C(O)NH₂, —C(O)NH(C₁₋₆alkyl), —C(O)N(C₁₋₆ alkyl)₂, —C(O)O(C₁₋₆ alkyl), —C(O)NH(CH₂CH₂O(C₁₋₃alkyl)), —C(O)NR_(b)R_(b), —C(O)(piperidinyl), —CH(OH)(C₃₋₆ cycloalkyl),—CH(OH)(phenyl), —CH(OH)(pyridyl), —S(O)₂(C₁₋₃ alkyl),—S(O)₂NR_(a)R_(a), or a cyclic group selected from phenyl, 5-to6-membered heteroaryl, and 5-to 7-membered heterocyclyl, wherein saidcyclic group is substituted with zero to 5 substituents independentlyselected from F, Cl, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, cyclopropyl, and—CN; R₃ is a bicyclic group selected from indolyl, benzofuranyl,benzo[b]thiophenyl, benzo[d]imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, imidazol[1,2-a]pyridinyl, thiazolo[4,5-b]pyridinyl,thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl,thiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl,4,5,6,7-tetrahydrobenzofuranyl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl,5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazolyl,5,6-dihydro-4H-cyclopenta[d]thiazolyl, indolizinyl,pyrrolo[1,2-a]pyrimidinyl, 6,7-dihydrothiazolo[5,4-c]pyridinyl,6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazinyl,4,5,6,7-tetrahydrobenzothiophenyl, furo[3,2-b]pyridinyl, andfuro[2,3-b]pyridinyl, each bicyclic group substituted with zero to 3R_(3a); R_(3a), at each occurrence, is independently: (i) F, Cl, —CN,—OH, C₁₋₃ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆hydroxy-deuteroalkyl, C₁₋₆ hydroxy-fluoroalkyl, C₁₋₆ alkoxy, C₁₋₃fluoroalkoxy, C₃₋₆ cycloalkyl, C₃₋₆ fluorocycloalkyl, 4-to 7-memberedheterocyclyl, —CH(OH)R_(y) wherein R_(y) is C₃₋₆ cycloalkyl, aryl,heteroaryl, or 4-to 7-membered heterocyclyl; (C₁₋₃ alkoxy)-(C₁₋₃alkylene), —(CH₂)₁₋₃NR_(a)R_(a), —(CH₂)₁₋₃NHS(O)₂(aryl),—O(CH₂)₁₋₃(aryl), —O(CH₂)₁₋₃(thiazolyl), —O(CH₂)₁₋₃(oxazolidinonyl),—O(CH₂)₁₋₃(amino isoxazolyl), —O(CH₂)₁₋₃(imidazolyl substituted withphenyl), C₁₋₆ hydroxyalkoxy, (C₁₋₃ alkoxy)-(C₁₋₆ alkoxy),—O(CH₂)₁₋₄O(aryl), —O(CH₂)₁₋₄O(CH₂)₁₋₃(aryl), —O(CH₂)₁₋₄NR_(a)R_(a),—O(CH₂)₁₋₃CHR_(a)NR_(a)(methoxy pyrimidinyl), —O(CH₂)₁₋₄NHS(O)₂(C₁₋₃alkyl), —O(CH₂)₁₋₄NHS(O)₂(aryl), —O(CH₂)₁₋₄C(O)OH, —O(CH₂)₁₋₄C(O)O(C₁₋₆alkyl), —O(CH₂)₁₋₄C(O)NR_(a)(CH₂)₀₋₃(aryl),—O(CH₂)₁₋₄C(O)NR_(a)(CH₂)₀₋₃(heteroaryl), —O(CH₂)₁₋₄C(O)(morpholinyl),—O(CH₂)₁₋₄OC(O)O(C₁₋₃ alkyl),—O(CH₂)₁₋₃CHR_(a)OC(O)NR_(a)(CH₂)₁₋₄C(O)NR_(a)R_(a),—CH₂CHR_(d)OC(O)NR_(a)(heteroaryl), —O(CH₂)₁₋₄OC(O)NR_(a)(heteroaryl),—O(imidazolyl substituted with aryl), —C(O)OH, —C(O)O(C₁₋₆ alkyl),—NR_(a)C(O)(furanyl), —NR_(a)C(O)(pyranyl), —NR_(a)C(O)O(C₁₋₆ alkyl),—NR_(a)C(O)O(CH₂)₁₋₄(aryl), —O(CH₂)₁₋₄NR_(a)C(O)O(C₁₋₆ alkyl),—O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄(tetrahydropyranyl),—O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄(aryl),—O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄(heteroaryl), or—O(CH₂)₁₋₄NR_(a)C(O)O(CH₂)₀₋₄(tetrahydrofuranyl), wherein each of saidaryl, heteroaryl, and 3- to 6-membered heterocyclyl is substituted withzero to 5 substituents independently selected from F, Cl, —CN, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₃ alkoxy, —OCF₃, —OCHF₂,—NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C(O)O(C₁₋₃ alkyl), C₁₋₃hydroxyalkoxy, phenyl, —CONR_(c)R_(c), and —S(O)₂NR_(c)R_(c); (ii)—CH(OH)CR_(h)R_(i)R_(j) wherein R_(h) and R_(i) are independently H, F,C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₃ alkoxy, C₁₋₃ fluoroalkoxy, or takentogether with the carbon atom to which they are attached, form C₃₋₈cycloalkyl or 4- to 7-membered heterocyclyl ring; and R_(j) is H, C₁₋₆alkyl, C₁₋₅ fluoroalkyl, (C₁₋₃ alkoxy)-(C₁₋₃ alkylene), C₃₋₈ cycloalkyl,C₃₋₈ heterocyclyl, aryl, or heteroaryl; (iii) —O(CH₂)₁₋₄NR_(a)S(O)₂(C₁₋₄alkyl) or —O(CH₂)₁₋₄NR_(a)S(O)₂R_(w), wherein R_(w) is aryl orheteroaryl, each substituted with zero to 2 substituents independentlyselected from F, Cl, cyano, C₁₋₃ alkyl, C₁₋₃ alkoxy, —OCF₃, —OCHF₂, andC₁₋₃ fluoroalkyl; or (iv) —O(CH₂)₁₋₄OC(O)NR_(a)R_(x),—OCH(R_(d))(CH₂)₁₋₃OC(O)NR_(a)R_(x),—OCR_(d)R_(d)(CH₂)₁₋₃OC(O)NR_(a)R_(x),—O(CH₂)₁₋₃CH(R_(d))OC(O)NR_(a)R_(x),—O(CH₂)₁₋₃CR_(d)R_(d)OC(O)NR_(a)R_(x),—OCH(R_(d))CH(R_(d))(CH₂)₀₋₂OC(O)NR_(a)R_(x), or—OCR_(d)R_(d)CR_(d)R_(d)(CH₂)₀₋₂OC(O)NR_(a)R_(x), wherein R_(x) isselected from H, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, aryl, heteroaryl, and—CH₂(heteroaryl), each aryl and heteroaryl substituted with zero to 2substituents independently selected from F, Cl, Br, —CN, —OH, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ hydroxy-deuteroalkyl,C₁₋₆ hydroxyalkoxy, C₁₋₆ hydroxy-fluoroalkoxy, C₁₋₃ alkoxy, —C(O)OH,—(CH₂)₀₋₃C(O)O(C₁₋₃ alkyl), —(CH₂)₁₋₃OP(O)(OH)₂, —CH₂(morpholinyl),—C(O)NH₂, —C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ alkyl)₂, —C(O)NR_(a)(C₁₋₆hydroxyalkyl), —C(O)NR_(b)R_(b), —S(O)₂NR_(a)R_(a), —NH₂, —NH(C₁₋₆alkyl), —NR_(a)(C₁₋₆ hydroxyalkyl), —N(C₁₋₆ alkyl)₂, —NR_(a)C(O)(C₁₋₆alkyl), —NR_(a)C(O)(chloro, fluorophenyl), —NR_(a)S(O)₂(C₁₋₃ alkyl),—C(O)NR_(a)(CH₂)₀₋₁ (hydroxymethyloxetanyl), —C(O)NR_(a)(CH₂)₀₋₁(hydroxymethyl C₃₋₆ cycloalkyl), —C(O)NR_(a)(CH₂)₀₋₁ (hydroxy C₃₋₆cycloalkyl), —C(O)NHCH₂C(CH₃)₂OP(O)(OH)₂, —C(O)(hydroxypiperidinyl),—C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl),—C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), pyrrolidinyl,morpholinyl, thiophenyl, methyl triazolyl, and oxazolidinonyl; R₄ is H,F, Cl, or —CH₃; R_(a), at each occurrence, is independently H,C₁₋₄alkyl, or C₁₋₄ fluoroalkyl; two R_(b) along with the nitrogen atomto which they are attached form a 4- to 7-membered heterocyclo ringhaving 1 to 2 nitrogen atoms and 0-1 oxygen or sulfur atoms; R_(c), ateach occurrence, is independently C₁₋₃ alkyl or C₁₋₃ hydroxyalkyl, ortwo R_(c) along with the nitrogen atom to which they are attached form aheterocyclyl or bicyclic heterocyclyl; R_(d), at each occurrence, isindependently C₁₋₆ alkyl, C₁₋₄ fluoroalkyl, C₁₋₆ hydroxyalkyl, (C₁₋₄alkoxy)-(C₁₋₃ alkylene), (C₁₋₂ fluoroalkoxy)-(C₁₋₂ alkylene), (C₃₋₆cycloalkyl)-(C₀₋₂ alkylene), aryl-(C₁₋₂ alkylene), heteroaryl-(C₁₋₂alkylene), aryloxy-(C₁₋₂ alkylene), aryl-CH₂O—(C₁₋₂ alkylene), orheteroaryloxy-(C₁₋₂ alkylene); and n is zero, 1, or
 2. 2. The compoundaccording to claim 1 having the structure of Formula (I) to Formula(IV):


3. The compound according to claim 1 or a salt thereof; wherein: R₁ is—OH, C₁₋₂ alkyl, —CHFCH₃, —CH═CH₂, C₁₋₃ alkoxy, C₁₋₂ fluoroalkoxy,—OCH₂CH₂OH, —CH₂O(C₁₋₂ alkyl), —CD₂OCD₃, —CH₂OCHF₂, —CF₂OCH₃,—CH₂O(phenyl), —CH(CH₃)OCH₃, —NH(CH₃), —N(CH₃)₂, —CH₂N(CH₃)₂, —C(O)NH₂,—C(O)NH(CH₃), —C(O)N(CH₃)₂, —C(O)NH(CH₂CH₂OH), —C(O)OCH₃, —CH(CH₃)OCH₃,cyclopropyl, furanyl, or —O(cyclopropyl); R₂, at each occurrence, isindependently H, F, Cl, —CN, —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃, —OCF₃,—CH₂OH, —CH₂CH₂OH, —CH(CH₃)OH, —C(CH₃)₂OH, —CH(OH)CH₂OH, —CH₂NH₂,—C(O)NH₂, —C(O)N(CH₃)₂, —C(O)(piperidinyl), —C(O)OCH₃,—C(O)NH(CH₂CH₂OCH₃), —CH(OH)(cyclopropyl), —CH(OH)(phenyl), —CH═CH₂,—C(CH₃)═CH₂, or —C≡CH; R₃ is:

R_(3a), at each occurrence, is independently: (i) F, Cl, —CN, —OH, —CH₃,—CF₃, —CHFC(CH₃)₃, cyclopropyl, —CH₂OH, —CD₂OH, —CH₂CH₂OH, —CH(OH)CH₃,—C(CH₃)₂OH, —CH(OH)C(CH₃)₃, —CD(OH)C(CH₃)₃, —CH(OH)CF₃, —CH(OH)CH₂CF₃,—CH(OH)(cyclopropyl), —CH(OH)(methylcyclopropyl),—CH(OH)(trifluoromethylcyclopropyl), —CH(OH)(cyclopropyl substitutedwith phenyl), —CH(OH)(cyclobutyl), —CH(OH)(methoxycyclobutyl),—CH(OH)(ethoxycarbonylcyclobutyl), —CH(OH)(trifluoromethylcyclobutyl),—CH(OH)(hydroxymethylcyclobutyl), —CH(OH)(cyclobutyl substituted withphenyl), —CH(OH)(cyclohexyl), —CH(OH)(methylcyclohexyl),—CH(OH)(phenyl), —CH(OH)(isopropylphenyl),—CH(OH)(trifluoromethylphenyl), —CH(OH)(fluoro, methoxyphenyl),—CH(OH)(pyridinyl), —CH(OH)(thiazolyl), —CH(OH)(tetrahydropyranyl),—CH(OH)(methyltetrahydropyranyl), —CH₂OCH₃, —CH₂N(CH₃)₂,—CH₂NHS(O)₂(phenyl), or —CH(OH)CH₂(phenyl); (ii) —OCH₃, —OCH₂CH₃,—OCH(CH₃)₂, —OCF₃, —OCHF₂, —OCH₂(phenyl), —OCH₂(thiazolyl),—OCH₂(oxazolidinonyl), —OCH₂(amino isoxazolyl), —OCH₂(imidazolylsubstituted with phenyl), —OCH₂CH₂OH, —OCH₂CH(CH₃)OH, —OCH₂CH₂OCH₃,—OCH(CH₃)CH₂OH, —OCH₂CH(OH)CH₃, —OCH(CH₃)CH(OH)CH₃, —OCH₂C(CH₃)₂OH,—OCH₂CH₂O(phenyl), —OCH₂CH₂OCH₂(phenyl), —OCH₂CH₂NH(CH₃),—OCH₂CH(CH₃)NH(methoxy pyrimidinyl), —OCH₂C(O)OH, —OCH₂C(O)OCH₃,—OCH₂C(O)OCH₂CH₃, —OCH₂C(O)OC(CH₃)₃, —OCH₂C(O)NH(phenyl),—OCH₂C(O)NHCH₂(phenyl), —OCH₂C(O)(morpholinyl),—OCH₂CH₂CH₂C(O)NH(pyridinyl), —OCH₂CH₂OC(O)OCH₃,—OCH₂CH(CH₃)OC(O)NHCH₂CH₂C(O)NH₂, —OCH₂CH(CH₂CH₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OC(CH₃)₃)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂(phenyl))OC(O)NH(pyridinyl),—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(pyrimidinyl), or—OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NH(methyl pyrimidinyl); (iii) —C(O)OH,—C(O)OCH₃, or —C(O)OC(CH₃)₃; (iv) —NHC(O)OCH₃, —NHC(O)OC(CH₃)₃,—NHC(O)OCH₂(phenyl), —NHC(O)OCH₂(tetrahydrofuranyl), or—NHC(O)O(tetrahydropyranyl); (v) —OCH₂CH₂NHC(O)OCH₃,—OCH₂CH₂NHC(O)O(tetrahydropyranyl), —OCH₂CH₂NHC(O)OCH₂(phenyl),—OCH₂CH₂NHC(O)O(methoxyphenyl), —OCH₂CH₂NHC(O)O(tetrahydrofuranyl),—OCH₂CH₂NHC(O)OCH₂(tetrahydrofuranyl), —OCH₂CH₂NHC(O)NH(pyridinyl),—OCH₂CH₂N(CH₃)C(O)NH(methylpyrimidinyl), or—OCH₂CH(CH₃)OC(O)OCH₂(aminopyridinyl); (vi) —OCH₂CH₂NHS(O)₂CH₃ or—OCH₂CH₂NHS(O)₂R_(w) wherein R_(w) is phenyl or pyridinyl, eachsubstituted with zero to 2 substituents independently selected from F,Cl, and —CH₃; or (vii) —OCH₂CH₂OC(O)NHR_(z), —OCH(CH₃)CH₂OC(O)NHR_(z),—OCH₂CH(CH₃)OC(O)NHR_(z), —OCH(CH₃)CH(CH₃)OC(O)NHR_(z),—OCH₂CH(CH₂O(isobutyl))OC(O)NHR_(z), —OCH₂CH(CH₂CH₃)OC(O)NHR_(z),—OCH₂CH(CH₂OCH₃)OC(O)NHR_(z), or —OCH₂CH(CH₂OCH₂CH(CH₃)₂)OC(O)NHR_(z)wherein R_(z) is H, —CH₂CF₃, phenyl, pyrrolyl, pyrazolyl, thiazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,oxadiazolyl, thiadiazolyl, indolyl, pyrrolo[2,3-b]pyridinyl,benzo[d]oxazolonyl, —CH₂(pyrazolyl), —CH₂(imidazolyl), or—CH₂(pyridinyl), each substituted with zero to 2 substituentsindependently selected from F, Cl, Br, —CN, —OH, —CH₃, —CH₂CH₂CH₃, —CF₃,—CH₂OH, —CD₂OH, —CH(CH₃)OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —C(CH₃)₂OH,—CH₂CH(CH₃)OH, —CH₂C(CH₃)₂OH, —CH₂CH₂C(O)OCH₃, —CH₂OP(O)(OH)₂,—CH₂CH₂OP(O)(OH)₂, —CH₂(morpholinyl), —OCH₃, —OCH₂CH₂OH, —OCH₂CH(CH₃)OH,—OCH₂C(CH₃)₂OH, —OCH₂CH₂C(CH₃)₂OH, —OCH(CH₃)CH₂OH, —OCH₂CH(OH)CH₂OH,—OCH₂CF₂OH, —OCH₂CF₂CH₂OH, —C(O)OH, —C(O)OCH₃, —C(O)NH₂, —C(O)NH(CH₃),—C(O)N(CH₃)₂, —C(O)NH(CH₂CH₂OH), —C(O)NH(CH₂CH(CH₃)OH),—C(O)NH(CH₂C(CH₃)₂OH), —C(O)NH(CH₂C(CH₃)₂CH₂OH),—C(O)NH(CH₂CH₂C(CH₃)₂OH), —C(O)N(CH₃)CH₂CH₂OH, —C(O)N(CH₃)CH₂C(CH₃)₂OH,—C(O)NHCH₂(hydroxymethyloxetanyl), —C(O)NH(hydroxymethylcyclobutyl),—C(O)NHCH₂(hydroxycyclobutyl), —C(O)NHCH₂(hydroxymethylcyclobutyl),—C(O)NHCH₂C(CH₃)₂OP(O)(OH)₂, —C(O)(hydroxypiperidinyl),—C(O)(hydroxypyrrolidinyl), —C(O)(hydroxymethylpyrrolidinyl),—C(O)(morpholinyl), —C(O)(hydroxymethylmorpholinyl), —NH₂, —N(CH₃)₂,—NHC(O)CH₃, —NHC(O)(chloro, fluorophenyl), —NH(CH₂C(CH₃)₂OH),—N(CH₃)S(O)₂CH₃, pyrrolidinyl, morpholinyl, thiophenyl, methyltriazolyl, and oxazolidinonyl; R₄ is H, F, or —CH₃; and p is zero, 1, 2,or
 3. 4. The compound according to claim 1 or a salt thereof, wherein:R₃ is:


5. The compound according to claim 1 having the structure of Formula(I):

or a salt thereof.
 6. The compound according to claim 5 or a saltthereof, wherein: R₁ is —OCH₃, —OCHF₂, —OCH₂CH₃, or —CH₂OCH₃; R₂, ateach occurrence, is independently H, F, Cl, —CN, —CH₃, —OCH₃, or —CH₂OH;and R₃ is:


7. The compound according to claim 1 or a salt thereof, wherein saidcompound is selected from Examples 1-129, 131-133, 135-152, 154-176,178-184, 186-189, 191-511, 516-624, 627-647, 658, 661-669, 671-702,708-731, 733-738, 740-768, and 805-837.
 8. The compound according toclaim 1 having the structure of Formula (II):

or a salt thereof.
 9. The compound according to claim 8 or a saltthereof, wherein: R₁ is —OH, —OCH₃, —OCH₂CH₃, —OCHF₂, —OCH₂CHF₂,—CH₂OCH₃, or —NH(CH₃); R₂, at each occurrence, is independently F, Cl,—CN, —CH₃, —CH₂OH, —CH₂F, —CHF₂, or —OCH₃; R₃ is:

and R_(3a), at each occurrence, is independently F, Cl, —CH₃, —OCH₃,—CH(OH)(trifluoromethylcyclobutyl), —OCH₂CH(CH₃)OC(O)NHR_(z), or—OCH(CH₃)CH(CH₃)OC(O)NHR_(z), wherein R_(z) is pyridinyl, pyrimidinyl,or benzo[d]oxazolonyl, each substituted with zero to 2 substituentsindependently selected from F, —OH, —CN, —CH₃, —CF₃, —CH₂OH, —CH₂CH₂OH,—OCH₂CH₂OH, —OCH₃, —CH₂CH(CH₃)OH, and —OCH₂CH₂C(CH₃)₂OH.
 10. Thecompound according to claim 1 or a salt thereof, wherein said compoundis selected from Examples 177, 185, 190, 512-515, 625-626, 648-657,659-660, and 769-804.
 11. A pharmaceutical composition, which comprisesa pharmaceutically acceptable carrier and a compound according to claim1 or a pharmaceutically acceptable salt thereof, alone or in combinationwith another therapeutic agent.
 12. A method for the treatment of athromboembolic disorder or the primary prophylaxis of a thromboembolicdisorder, which comprises the steps of administering to a patient inneed thereof a therapeutically effective amount of a compound accordingto claim 1 or a pharmaceutically acceptable salt thereof, wherein thethromboembolic disorder is selected from the group consisting ofarterial cardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, and thromboembolic disorders in the chambersof the heart or in the peripheral circulation.
 13. The method accordingto claim 8 wherein the thromboembolic disorder is selected from thegroup consisting of unstable angina, an acute coronary syndrome, atrialfibrillation, myocardial infarction, transient ischemic attack, stroke,atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, and procedures in which blood is exposedto an artificial surface that promotes thrombosis.
 14. A method ofinhibiting or preventing platelet aggregation, which comprises the stepof administering to a subject in need thereof a therapeuticallyeffective amount of a compound according to claim 1 or a salt thereof.